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Heiat M, Javanbakht M, Jafari D, Poudineh M, Heydari F, Sharafi H, Alavian SM. Correlation of IL-10 and IL18 with the development of liver cirrhosis associated with hepatitis B virus infection: A systematic review. Cytokine 2025; 186:156818. [PMID: 39671883 DOI: 10.1016/j.cyto.2024.156818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 10/02/2024] [Accepted: 11/16/2024] [Indexed: 12/15/2024]
Abstract
BACKGROUND Patients who have been infected with the Hepatitis B virus (HBV) are susceptible to developing liver cirrhosis (LC) and hepatocellular carcinoma (HCC). The objective of this systematic review was to comprehensively scrutinize the existing evidence concerning the association between host genetic polymorphisms and HBV-associated LC. METHODS We searched databases of PubMed, Scopus, and Web of Science for relevant articles published from building databases to 25 October 2023. RESULT We detected 104 relevant articles, relating to 84 individuals genes. Nine genes had the strong evidence of correlation, including IL-10, IL-18, IL-1B, TGF- β, TLR3, STAT4, IL-1RN, Tim3, and IFN receptors. A positive correlation was found for 33 genes but this data had not yet been replicated, 11 genes had limited or mixed evidence of a correlation, and 34 genes indicated no correlation. IL-10 and IL-18 had the most evidence of correlation. There was a notable amount of diversity in both the design and method of studies and data quality. CONCLUSION IL-10 and IL-18 had the most evidence of correlation. There was a notable amount of diversity in both the design and method of studies and data quality. It is of necessary to take into account the fundamental mechanism behind these associations and discern those that are confounded by the coexistence of other LC/HCC risk factors and response to therapy. These results are expected to guide future studies on the genetic susceptibility of HBV-related LC/HCC.
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Affiliation(s)
- Mohammad Heiat
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Mohammad Javanbakht
- Nephrology and Urology Research Center, Clinical Science Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Davood Jafari
- Department of Immunology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mohadeseh Poudineh
- Student Research Committee, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Fatemeh Heydari
- Student Research Committee, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | | | - Seyed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
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Yadav S, Prasannan A, Venkatachalam K, Binesh A. Exploring the mechanism and crosstalk between IL-6 and IL- 1β on M2 macrophages under metabolic stress conditions. Cytokine 2025; 186:156852. [PMID: 39765025 DOI: 10.1016/j.cyto.2024.156852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 12/29/2024] [Accepted: 12/31/2024] [Indexed: 01/14/2025]
Abstract
Macrophages are highly variable immune cells that are important in controlling inflammation and maintaining tissue balance. The ability to polarize into two major types-M1, promoting inflammation, and M2, resolving inflammation and contributing to tissue repair-determines their specific roles in health and disease. M2 macrophages are particularly important for reducing inflammation and promoting tissue regeneration, but their function is shaped mainly by surrounding cells. This is evident in obesity, diabetes, and chronic inflammation. Although many cytokines regulate macrophage polarization, interleukin-6 (IL-6) and interleukin-1β (IL-1β) are major players, but their effects on M2 macrophage behavior under metabolic stress remain unclear. This study describes the intricacies within M2 macrophages concerning IL-6 and IL-1β signaling when under metabolic stress. Though, more frequently than not, IL-6 is labelled as pro-inflammatory, it can also behave as an anti-inflammatory mediator. On the other hand, IL-1β is the main pro-inflammatory agent, particularly in metabolic disorders. The relationship between these cytokines and the macrophages is mediated through important pathways such as JAK/STAT and NFκB, which get perturbed by metabolic stress. Therefore, metabolic stress also alters the functional parameters of macrophages, including alterations in mitochondrial metabolism, glycolytic and oxidative metabolism. Phosphorylation alters the kinetics involved in energy consumption and affects their polarization and their function. However, it has been suggested that IL-6 and IL-1β may work in concert or competition when inducing M2 polarization and, importantly, implicate cytokine release, phagocytic activity, and tissue repair processes. In this review, we discuss the recent literature on the participation of IL-6 and IL-1β cytokines in macrophage polarization and how metabolic stress changes cytokine functions and synergistic relations. A better understanding of these cytokines would serve as an important step toward exploring alternative antiviral strategies directed against metabolic disturbance and, hence, approve further endeavors.
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Affiliation(s)
- Shawna Yadav
- Department of Basic Sciences, Institute of Fisheries Post Graduate Studies, Tamil Nadu Dr. J. Jayalalithaa Fisheries University (TNJFU), OMR Campus, Vaniyanchavadi, Chennai 603103, Tamil Nadu, India
| | - Anusha Prasannan
- Department of Basic Sciences, Institute of Fisheries Post Graduate Studies, Tamil Nadu Dr. J. Jayalalithaa Fisheries University (TNJFU), OMR Campus, Vaniyanchavadi, Chennai 603103, Tamil Nadu, India
| | - Kaliyamurthi Venkatachalam
- Department of Basic Sciences, Institute of Fisheries Post Graduate Studies, Tamil Nadu Dr. J. Jayalalithaa Fisheries University (TNJFU), OMR Campus, Vaniyanchavadi, Chennai 603103, Tamil Nadu, India
| | - Ambika Binesh
- Department of Basic Sciences, Institute of Fisheries Post Graduate Studies, Tamil Nadu Dr. J. Jayalalithaa Fisheries University (TNJFU), OMR Campus, Vaniyanchavadi, Chennai 603103, Tamil Nadu, India.
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Fang Z, Jiang J, Zheng X. Interleukin-1 receptor antagonist: An alternative therapy for cancer treatment. Life Sci 2023; 335:122276. [PMID: 37977354 DOI: 10.1016/j.lfs.2023.122276] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 11/03/2023] [Accepted: 11/14/2023] [Indexed: 11/19/2023]
Abstract
The interleukin-1 receptor antagonist (IL-1Ra) is an anti-inflammatory cytokine and a naturally occurring antagonist of the IL-1 receptor. It effectively counteracts the IL-1 signaling pathway mediated by IL-1α/β. Over the past few decades, accumulating evidence has suggested that IL-1 signaling plays an essential role in tumor formation, growth, and metastasis. Significantly, anakinra, the first United States Food and Drug Administration (FDA)-approved IL-1Ra drug, has demonstrated promising antitumor effects in animal studies. Numerous clinical trials have subsequently incorporated anakinra into their cancer treatment protocols. In this review, we comprehensively discuss the research progress on the role of IL-1 in tumors and summarize the significant contribution of IL-1Ra (anakinra) to tumor immunity. Additionally, we analyze the potential value of IL-1Ra as a biomarker from a clinical perspective. This review is aimed to highlight the important link between inflammation and cancer and provide potential drug targets for future cancer therapy.
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Affiliation(s)
- Zhang Fang
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, Jiangsu, China; Institute for Cell Therapy of Soochow University, Changzhou, Jiangsu, China
| | - Jingting Jiang
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, Jiangsu, China; Institute for Cell Therapy of Soochow University, Changzhou, Jiangsu, China.
| | - Xiao Zheng
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, Jiangsu, China; Institute for Cell Therapy of Soochow University, Changzhou, Jiangsu, China.
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Naidoo L, Arumugam T, Ramsuran V. Host Genetic Impact on Infectious Diseases among Different Ethnic Groups. ADVANCED GENETICS (HOBOKEN, N.J.) 2023; 4:2300181. [PMID: 38099246 PMCID: PMC10716055 DOI: 10.1002/ggn2.202300181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 09/11/2023] [Indexed: 12/17/2023]
Abstract
Infectious diseases such as malaria, tuberculosis (TB), human immunodeficiency virus (HIV), and the coronavirus disease of 2019 (COVID-19) are problematic globally, with high prevalence particularly in Africa, attributing to most of the death rates. There have been immense efforts toward developing effective preventative and therapeutic strategies for these pathogens globally, however, some remain uncured. Disease susceptibility and progression for malaria, TB, HIV, and COVID-19 vary among individuals and are attributed to precautionary measures, environment, host, and pathogen genetics. While studying individuals with similar attributes, it is suggested that host genetics contributes to most of an individual's susceptibility to disease. Several host genes are identified to associate with these pathogens. Interestingly, many of these genes and polymorphisms are common across diseases. This paper analyzes genes and genetic variations within host genes associated with HIV, TB, malaria, and COVID-19 among different ethnic groups. The differences in host-pathogen interaction among these groups, particularly of Caucasian and African descent, and which gene polymorphisms are prevalent in an African population that possesses protection or risk to disease are reviewed. The information in this review could potentially help develop personalized treatment that could effectively combat the high disease burden in Africa.
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Affiliation(s)
- Lisa Naidoo
- School of Laboratory Medicine and Medical SciencesCollege of Health SciencesUniversity of KwaZulu‐NatalDurban4041South Africa
| | - Thilona Arumugam
- School of Laboratory Medicine and Medical SciencesCollege of Health SciencesUniversity of KwaZulu‐NatalDurban4041South Africa
| | - Veron Ramsuran
- School of Laboratory Medicine and Medical SciencesCollege of Health SciencesUniversity of KwaZulu‐NatalDurban4041South Africa
- Centre for the AIDS Programme of Research in South Africa (CAPRISA)University of KwaZulu‐NatalDurban4041South Africa
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Madison AA, Renna M, Andridge R, Peng J, Shrout MR, Sheridan J, Lustberg M, Ramaswamy B, Wesolowski R, Williams NO, Noonan AM, Reinbolt RE, Stover DG, Cherian MA, Malarkey WB, Kiecolt-Glaser JK. Conflicts hurt: social stress predicts elevated pain and sadness after mild inflammatory increases. Pain 2023; 164:1985-1994. [PMID: 36943254 PMCID: PMC10440304 DOI: 10.1097/j.pain.0000000000002894] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 02/07/2023] [Indexed: 03/23/2023]
Abstract
ABSTRACT Individuals respond differently to inflammation. Pain, sadness, and fatigue are common correlates of inflammation among breast cancer survivors. Stress may predict response intensity. This study tested whether breast cancer survivors with greater exposure to acute or chronic social or nonsocial stress had larger increases in pain, sadness, and fatigue during an acute inflammatory response. In total, 156 postmenopausal breast cancer survivors (ages 36-78 years, stage I-IIIA, 1-9 years posttreatment) were randomized to either a typhoid vaccine/saline placebo or the placebo/vaccine sequence, which they received at 2 separate visits at least 1 month apart. Survivors had their blood drawn every 90 minutes for the next 8 hours postinjection to assess levels of interleukin-6 and interleukin-1 receptor antagonist (IL-1Ra). Shortly after each blood draw, they rated their current levels of pain, sadness, and fatigue. Women also completed the Test of Negative Social Exchange to assess chronic social stress and the Trier Inventory of Chronic Stressors screen to index chronic general stress. At each visit, a trained experimenter administered the Daily Inventory of Stressful Events to assess social and nonsocial stress exposure within the past 24 hours. After statistical adjustment for relevant demographic and behavioral covariates, the most consistent results were that survivors who reported more chronic social stress reported more pain and sadness in response to IL-1Ra increases. Frequent and ongoing social stress may sensitize the nervous system to the effects of inflammation, with potential implications for chronic pain and depression risk among breast cancer survivors.
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Affiliation(s)
- Annelise A Madison
- Institute for Behavioral Medicine Research, The Ohio State University College of Medicine, Columbus, OH, United States
- Department of Psychology, The Ohio State University, Columbus, OH, United States
| | - Megan Renna
- School of Psychology, University of Southern Mississippi, Hattiesburg, MS, United States
| | - Rebecca Andridge
- Division of Biostatistics, The Ohio State University, Columbus, OH, United States
| | - Juan Peng
- Division of Biostatistics, The Ohio State University, Columbus, OH, United States
| | - M Rosie Shrout
- College of Health and Human Sciences, Purdue University, West Lafayette, IN, United States
| | - John Sheridan
- Institute for Behavioral Medicine Research, The Ohio State University College of Medicine, Columbus, OH, United States
- Division of Biosciences, The Ohio State University College of Dentistry, Columbus, OH, United States
| | | | - Bhuvaneswari Ramaswamy
- Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, United States
- Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, United States
| | - Robert Wesolowski
- Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, United States
- Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, United States
| | - Nicole O Williams
- Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, United States
- Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, United States
| | - Anne M Noonan
- Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, United States
- Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, United States
| | - Raquel E Reinbolt
- Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, United States
- Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, United States
| | - Daniel G Stover
- Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, United States
- Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, United States
| | - Mathew A Cherian
- Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, United States
- Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, United States
| | - William B Malarkey
- Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, United States
| | - Janice K Kiecolt-Glaser
- Institute for Behavioral Medicine Research, The Ohio State University College of Medicine, Columbus, OH, United States
- Department of Psychiatry and Behavioral Health, The Ohio State University College of Medicine, Columbus, OH, United States
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Understanding Ocular Surface Inflammation in Tears Before and After Autologous Cultivated Limbal Epithelial Stem Cell Transplantation. Ophthalmol Ther 2023; 12:1097-1107. [PMID: 36708444 PMCID: PMC10011244 DOI: 10.1007/s40123-023-00656-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 01/12/2023] [Indexed: 01/29/2023] Open
Abstract
INTRODUCTION We aimed to determine the expression of inflammatory cytokines in the tears of patients with unilateral total limbal stem cell deficiency (TLSCD) caused by chemical burns before and after autologous cultivated limbal epithelial stem cell transplantation (CLET). METHODS Tear samples were collected from both eyes of 23 patients with unilateral TLSCD and 11 healthy controls, at fixed timepoints before and after CLET. Dissolved molecules were extracted from Schirmer's strips using a standardised method and analysed on an array plate of ten inflammatory cytokines (V-Plex Proinflammatory Panel 1 Human Kit, MSD). RESULTS IL1β expression was significantly elevated in the TLSCD eye compared with the unaffected eye at baseline (p < 0.0001) but decreased to normal 3 months post-CLET (p = 0.22). IL6 and IL8 were unaffected at baseline but significantly elevated in the TLSCD eyes at 1 month post-CLET (p = 0.001 and p < 0.0001, respectively). IL6 returned to normal at 3 months and IL8 at 6 months post-CLET. There was a significant renewed increase in IL1β, IL6 and IL8 expression at 12 months post-CLET (p < 0.0001, p = 0.0001 and p = 0.0003, respectively). IFNγ, IL10 and IL12p70 expression were significantly reduced in both eyes of patients with unilateral TLSCD at all timepoints. CONCLUSION IL1β is a specific marker of inflammation in TLSCD eyes that could be therapeutically targeted pre-CLET to improve stem cell engraftment. At 12 months post-CLET the spike in levels of IL1β, IL6 and IL8 coincides with cessation of topical steroids, suggesting ongoing subclinical inflammation. We therefore recommend not discontinuing topical steroid treatment in cases where penetrating keratoplasty is indicated; however, further investigation is needed to ascertain this. TRIAL REGISTRATION European Union Drug Regulating Authorities Clinical Trials Database (EuDRACT 2011-000608-16); ISRCTN (International Standard Randomised Controlled Trial Number (isrctn51772481).
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Affiliation(s)
- Alberto Mantovani
- From IRCCS Humanitas Research Hospital, Rozzano, and the Department of Biomedical Sciences, Humanitas University, Pieve Emanuele - both in Milan (A.M., C.G.); and William Harvey Research Institute, Queen Mary University, London (A.M.)
| | - Cecilia Garlanda
- From IRCCS Humanitas Research Hospital, Rozzano, and the Department of Biomedical Sciences, Humanitas University, Pieve Emanuele - both in Milan (A.M., C.G.); and William Harvey Research Institute, Queen Mary University, London (A.M.)
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Suriguga S, Li M, Luangmonkong T, Boersema M, de Jong KP, Oosterhuis D, Gorter AR, Beljaars L, Olinga P. Distinct responses between healthy and cirrhotic human livers upon lipopolysaccharide challenge: possible implications for acute-on-chronic liver failure. Am J Physiol Gastrointest Liver Physiol 2022; 323:G114-G125. [PMID: 35727919 DOI: 10.1152/ajpgi.00243.2021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Patients with acute-on-chronic liver failure (ACLF) are at risk of developing acute hepatic decompensation and organ failures with an unraveled complex mechanism. An altered immune response toward insults in cirrhotic compared with healthy livers may contribute to the ACLF development. Therefore, we aim to investigate the differences in inflammatory responses between cirrhotic and healthy livers using human precision-cut liver slices (PCLSs) upon the lipopolysaccharide (LPS) challenge. PCLSs prepared from livers of patients with cirrhosis or healthy donors of liver transplantation were incubated ex vivo with or without LPS for up to 48 h. Viability test, qRT-PCR, and multiplex cytokine assay were performed. Regulation of the LPS receptors during incubation or with LPS challenge differed between healthy versus cirrhotic PCLSs. LPS upregulated TLR-2 in healthy PCLSs solely (P < 0.01). Culturing for 48 h induced a stronger inflammatory response in the cirrhotic than healthy PCLS. Upon LPS stimulation, cirrhotic PCLSs secreted more proinflammatory cytokines (IL-8, IL-6, TNF-α, eotaxin, and VEGF) significantly and less anti-inflammatory cytokine (IL-1ra) than those of healthy. In summary, cirrhotic PCLSs released more proinflammatory and less anti-inflammatory cytokines after LPS stimuli than healthy, leading to dysregulated inflammatory response. These events could possibly resemble the liver immune response in ACLF.NEW & NOTEWORTHY Precision-cut liver slices (PCLSs) model provides a unique platform to investigate the different immune responses of healthy versus cirrhotic livers in humans. Our data show that cirrhotic PCLSs exhibit excessive inflammatory response accompanied by a lower anti-inflammatory cytokine release in response to LPS; a better understanding of this alteration may guide the novel therapeutic approaches to mitigate the excessive inflammation during the onset of acute-on-chronic liver failure.
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Affiliation(s)
- Su Suriguga
- Key Laboratory of Clinical Diagnosis and Treatment Technology in Animal Disease, Ministry of Agriculture, College of Veterinary Medicine, Inner Mongolia Agricultural University, Hohhot, People's Republic of China.,Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Mei Li
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Theerut Luangmonkong
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, The Netherlands.,Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
| | - Miriam Boersema
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Koert P de Jong
- Department of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Dorenda Oosterhuis
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - A R Gorter
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Leonie Beljaars
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Peter Olinga
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, The Netherlands
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Kiecolt-Glaser JK, Renna M, Peng J, Sheridan J, Lustberg M, Ramaswamy B, Wesolowski R, VanDeusen JB, Williams NO, Sardesai SD, Noonan AM, Reinbolt RE, Stover DG, Cherian MA, Malarkey WB, Andridge R. Breast cancer survivors' typhoid vaccine responses: Chemotherapy, obesity, and fitness make a difference. Brain Behav Immun 2022; 103:1-9. [PMID: 35378230 PMCID: PMC9149127 DOI: 10.1016/j.bbi.2022.03.019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 03/24/2022] [Accepted: 03/31/2022] [Indexed: 02/05/2023] Open
Abstract
PURPOSE To investigate breast cancer survivors' inflammatory responses to typhoid vaccine as a window into their innate immune response to novel pathogens. METHODS This double-blind crossover trial randomized 158 breast cancer survivors to either the vaccine/saline placebo or the placebo/vaccine sequence. The relative contributions of age, cardiorespiratory fitness (VO2peak), type of cancer treatment, central obesity, and depression to interleukin (IL)-6, IL-1 receptor antagonist (IL-1Ra), and WBC vaccine responses were assessed pre-injection and 1.5, 3, 4.5, 6, and 7.5 h post-injection. RESULTS The vaccine produced larger IL-6, IL-1Ra, and WBC responses than placebo, ps < 0.0001. Prior chemotherapy, higher central obesity, and lower VO2peak were associated with smaller vaccine responses after controlling for baseline inflammation. Vaccine response was summarized by the percent increase in area under the curve (IL-6, WBC) or average post-injection mean (IL-1Ra) for vaccine relative to placebo. Women who received chemotherapy had smaller vaccine responses than women who did not for both IL-6 (44% vs 78%, p <.001) and WBC (26% vs 40%, p <.001); IL-1ra response was not significantly moderated by chemotherapy. Women whose central adiposity was one standard deviation above the mean had smaller vaccine responses than women with average adiposity for IL-6 (33% vs 54%, p <.001), WBC (20% vs 30%, p <.001), and IL-1Ra (2.0% vs 3.2%, p <.001). Women with an average level of VO2peak had smaller vaccine responses than women whose VO2peak was one standard deviation above the mean for IL-6 (54% vs 73%, p <.001), WBC (30% vs 40%, p <.001), and IL-1Ra (3.2% vs. 4.1%, p = 0.01). Age and depression did not significantly moderate vaccine responses. CONCLUSIONS This study provided novel data on chemotherapy's longer-term adverse immune consequences. The data also have an important public health message: even relatively low levels of fitness can benefit the innate immune response to a vaccine.
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Affiliation(s)
- Janice K. Kiecolt-Glaser
- Institute for Behavioral Medicine Research, The Ohio State University College of Medicine, Columbus, OH,Department of Psychiatry and Behavioral Health, The Ohio State University College of Medicine, Columbus, OH
| | - Megan Renna
- School of Psychology, University of Southern Mississippi, Hattiesburg, MS
| | - Juan Peng
- Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, College of Medicine, Columbus, OH
| | - John Sheridan
- Institute for Behavioral Medicine Research, The Ohio State University College of Medicine, Columbus, OH,Division of Biosciences, The Ohio State University College of Dentistry, Columbus, OH
| | | | - Bhuvaneswari Ramaswamy
- Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH,Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH
| | - Robert Wesolowski
- Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH,Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH
| | - Jeffrey B. VanDeusen
- Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH,Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH
| | - Nicole O. Williams
- Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH,Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH
| | - Sagar D. Sardesai
- Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH,Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH
| | - Anne M. Noonan
- Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH,Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH
| | - Raquel E. Reinbolt
- Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH,Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH
| | - Daniel G. Stover
- Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH,Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH
| | - Mathew A. Cherian
- Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH,Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH
| | - William B. Malarkey
- Institute for Behavioral Medicine Research, The Ohio State University College of Medicine, Columbus, OH,Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH
| | - Rebecca Andridge
- Division of Biostatistics, College of Public Health, The Ohio State University, Columbus, OH
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10
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Straat ME, Martinez-Tellez B, Janssen LG, van Veen S, van Eenige R, Kharagjitsing AV, van den Berg SA, de Rijke YB, Haks MC, Rensen PC, Boon MR. The effect of cold exposure on circulating transcript levels of immune genes in Dutch South Asian and Dutch Europid men. J Therm Biol 2022; 107:103259. [DOI: 10.1016/j.jtherbio.2022.103259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 01/06/2022] [Accepted: 05/17/2022] [Indexed: 11/29/2022]
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The Effects of 21-Day General Rehabilitation after Hip or Knee Surgical Implantation on Plasma Levels of Selected Interleukins, VEGF, TNF-α, PDGF-BB, and Eotaxin-1. Biomolecules 2022; 12:biom12050605. [PMID: 35625533 PMCID: PMC9139046 DOI: 10.3390/biom12050605] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 04/11/2022] [Accepted: 04/17/2022] [Indexed: 02/01/2023] Open
Abstract
Rehabilitation in osteoarthritis (OA) patients aims to reduce joint pain and stiffness, preserve or improve joint mobility, and improve patients’ quality of life. This study evaluated the effects of the 21-day individually adjusted general rehabilitation program in 36 OA patients 90 days after hip or knee replacement on selected interleukins (IL) and cytokines using the Bio-Plex® Luminex® system. Serum concentrations of almost all selected anti/pro-inflammatory markers: IL-1 receptor antagonist (IL-1RA), IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, IL-15, and of some chemokines: macrophage inflammatory protein-1 alpha (MIP-1α/CCL3), and RANTES/CCL5, and of eotaxin-1/CCL11, the vascular endothelial growth factor (VEGF) significantly increased, whereas basic fibroblast growth factor (FGF basic) significantly decreased after the 21-day general rehabilitation. The levels of interferon-γ induced protein 10 (IP-10), MIP-1β/CCL4, macrophage/monocyte chemoattractant protein-1 (MCP-1/CCL2 (MCAF)), granulocyte macrophage-colony stimulating factor (GM-CSF), platelet-derived growth factor-BB (PDGF-BB), and granulocyte colony-stimulating factor (G-CSF) remained unchanged. There were no changes in pro-inflammatory cytokines levels: tumor necrosis factor-alpha (TNF-α), interferon-γ (IFN-γ), and IL-12 (p70)) after the 21-day general rehabilitation, indicating the stable and controlled inflammatory status of osteoarthritis patients. Significantly higher levels of anti-inflammatory factors after 21 days of moderate physical activity confirm the beneficial outcome of the applied therapy. The increased level of IL-6 after the rehabilitation may reflect its anti-inflammatory effect in osteoarthritis patients.
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Nakada T, Mager DE. Systems model identifies baseline cytokine concentrations as potential predictors of rheumatoid arthritis inflammatory response to biologics. Br J Pharmacol 2022; 179:4063-4077. [PMID: 35355255 DOI: 10.1111/bph.15845] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 01/21/2022] [Accepted: 03/08/2022] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND AND PURPOSE Circulating cytokines are central pathological mediators of inflammatory autoimmune diseases like rheumatoid arthritis (RA). Immunological diversity in patients might contribute to inadequate responses to biological drugs. To address this therapeutic challenge, we developed a mathematical model that simultaneously describes temporal patterns of drug disposition for several biologics and their corresponding targeted cytokines, which were linked to triggering inflammatory responses. EXPERIMENTAL APPROACH A modeling framework was applied to RA-relevant cytokines regulating C-reactive protein (CRP) as an inflammatory marker. Clinical data were extracted from the literature for anakinra, canakinumab, infliximab, secukinumab, and tocilizumab, along with their corresponding cytokines: interleukin-1 receptor antagonist, IL-1β, tumor necrosis factor α (TNFα), IL-17A, and IL-6 receptor (IL-6R). Based on prior knowledge of regulatory mechanisms, cytokines were integrated with CRP profiles. KEY RESULTS The model well captured all serum concentration-time profiles of cytokines and CRP ratios to respective baselines following drug treatment with good precision. On external validation, reasonable model-performance on CRP dynamics, including rebound effects, was confirmed with clinical data not used in model development. Model-based simulations demonstrated that serum infliximab concentrations were accurately recapitulated in both a dose- and baseline TNFα-dependent manner. Furthermore, high baseline profiles of both IL-1β and/or targeted cytokines could be predictors of poor responses to biologics targeting TNFα and IL-6R, although the impact of IL-1β must be carefully interpreted. CONCLUSIONS AND IMPLICATION Our model provides a quantitative platform to guide targeting and dosing strategies, including combination and/or sequential therapy, according to distinct baseline cytokine patterns in RA patients.
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Affiliation(s)
- Tomohisa Nakada
- Department of Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA.,Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Kanagawa, Japan
| | - Donald E Mager
- Department of Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA.,Enhanced Pharmacodynamics, LLC, Buffalo, NY, USA
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Frühbeck G, Catalán V, Ramírez B, Valentí V, Becerril S, Rodríguez A, Moncada R, Baixauli J, Silva C, Escalada J, Gómez-Ambrosi J. Serum Levels of IL-1 RA Increase with Obesity and Type 2 Diabetes in Relation to Adipose Tissue Dysfunction and are Reduced After Bariatric Surgery in Parallel to Adiposity. J Inflamm Res 2022; 15:1331-1345. [PMID: 35237063 PMCID: PMC8884708 DOI: 10.2147/jir.s354095] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 02/15/2022] [Indexed: 12/22/2022] Open
Abstract
Background Excess adiposity leads to a dysfunctional adipose tissue that contributes to the development of obesity-associated comorbidities such as type 2 diabetes (T2D). Interleukin-1 receptor antagonist (IL-1RA) is a naturally occurring antagonist of the IL-1 receptor with anti-inflammatory properties. The aim of the present study was to compare the circulating concentrations of IL-1RA and its mRNA expression in visceral adipose tissue (VAT) in subjects with normal weight (NW), obesity with normoglycemia (OB-NG), or obesity with impaired glucose tolerance or T2D (OB-IGT&T2D) and to analyze the effect of changes in body fat percentage (BF%) on IL-1RA levels. Methods Serum concentrations of IL-1RA were measured in 156 volunteers. Expression of IL1RN mRNA in VAT obtained from 36 individuals was determined. In addition, the concentrations of IL-1RA were measured before and after weight gain as well as weight loss following a dietetic program or Roux-en-Y gastric bypass (RYGB). Results Serum levels of IL-1RA were significantly increased in individuals with obesity, being further increased in the OB-IGT&T2D group (NW 440 ± 316, OB-NG 899 ± 562, OB-IGT&T2D 1265 ± 739 pg/mL; P<0.001) and associated with markers of inflammation and fatty liver. IL1RN mRNA expression in VAT was significantly increased in the OB-IGT&T2D group and correlated in the global cohort with the mRNA expression of SPP1, CCL2, CD68, and MMP9. Levels of IL-1RA were not modified after modest changes in BF%, but RYGB-induced weight loss significantly decreased IL-1RA concentrations from 1233 ± 1009 to 660 ± 538 pg/mL (P<0.001). Conclusion Serum IL-1RA concentrations are increased in patients with obesity being further elevated in obesity-associated IGT and T2D in association with markers of adipose tissue dysfunction. The mRNA expression of IL1RN is markedly increased in VAT of subjects with obesity and T2D in relation with genes involved in macrophage recruitment, inflammation and matrix remodeling. Serum IL-1RA concentrations are reduced when a notable amount of BF% is loss. Measurement of IL-1RA is an excellent biomarker of adipose tissue dysfunction in obesity-associated metabolic alterations.
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Affiliation(s)
- Gema Frühbeck
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain
- Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, Pamplona, Spain
| | - Victoria Catalán
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain
| | - Beatriz Ramírez
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain
| | - Víctor Valentí
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain
- Department of Surgery, Clínica Universidad de Navarra, Pamplona, Spain
| | - Sara Becerril
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain
| | - Amaia Rodríguez
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain
| | - Rafael Moncada
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain
- Department of Anesthesia, Clínica Universidad de Navarra, Pamplona, Spain
| | - Jorge Baixauli
- Department of Surgery, Clínica Universidad de Navarra, Pamplona, Spain
| | - Camilo Silva
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain
- Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, Pamplona, Spain
| | - Javier Escalada
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, Pamplona, Spain
| | - Javier Gómez-Ambrosi
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain
- Correspondence: Javier Gómez-Ambrosi, Metabolic Research Laboratory, Clínica Universidad de Navarra, Irunlarrea 1, Pamplona, 31008, Spain, Tel +34 948 425600 (ext. 806567), Email
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Kim YO, Kim HI, Jung BK. Pattern of change of C-reactive protein levels and its clinical implication in patients with acute poisoning. SAGE Open Med 2022; 10:20503121211073227. [PMID: 35127097 PMCID: PMC8808020 DOI: 10.1177/20503121211073227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 12/21/2021] [Indexed: 11/26/2022] Open
Abstract
Objectives: C-reactive protein is well known as an inflammatory indicator in injury, infection, and cancer. However, little is known about its role in poisoning. C-reactive protein levels first increase and then decrease within several days during poisoning management. This study aimed to verify the C-reactive protein change pattern and its clinical co-infection possibility in patients with poisoning. Methods: Daily C-reactive protein levels of the patients with poisoning, who were admitted for more than 5 days, were measured. Microbial cultures were conducted, and fever (⩾38°C) and infection-related symptoms were investigated. Results: In the enrolled 56 patients, the initial median C-reactive protein levels at hospital day 1, 2, 3, 4, and 5 were 0.28, 4.85, 10.91, 10.57, and 6.68 mg/dL, respectively. C-reactive protein level was the highest at hospital day 3 and decreased thereafter. No statistical difference was observed in the daily and maximal C-reactive protein levels between the culture-positive and culture-negative groups. The levels at hospital days 3–5 and the maximal level were 8.4, 9.2, 5.49, and 11.02 mg/dL, respectively, in non-fever group. The levels at hospital days 3–5 and the maximal level were 7.4, 9.2, 4.74, and 10.81 mg/dL, respectively, in non-symptoms group. Levels at hospital days 3–5 and the maximal level were 5.21, 4.93, 3.7, and 5.28 mg/dL, respectively, in all-negative (culture-negative without fever or infection symptoms) group. Conclusions: Acute rise and fall of C-reactive protein levels can be observed in the infection-unlikely patients with poisoning. The levels were similar to bacterial infection levels, possibly due to the drug reaction itself, rather than for superimposed infections.
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Affiliation(s)
- Yong Oh Kim
- Department of Emergency Medicine, College of Medicine, Dankook University, Cheonan, Korea
| | - Hyung Il Kim
- Department of Emergency Medicine, College of Medicine, Dankook University, Cheonan, Korea
- Department of Emergency Medicine, School of Medicine, Kangwon National University, Chuncheon, Korea
| | - Bo Kyeung Jung
- Department of Laboratory Medicine, College of Medicine, Dankook University, Cheonan, Korea
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Karaba AH, Zhou W, Hsieh LL, Figueroa A, Massaccesi G, Rothman RE, Fenstermacher KZJ, Sauer L, Shaw-Saliba K, Blair PW, Robinson ML, Leung S, Wesson R, Alachkar N, El-Diwany R, Ji H, Cox AL. Differential Cytokine Signatures of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Influenza Infection Highlight Key Differences in Pathobiology. Clin Infect Dis 2022; 74:254-262. [PMID: 34013339 PMCID: PMC8243556 DOI: 10.1093/cid/ciab376] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Several inflammatory cytokines are upregulated in severe coronavirus disease 2019 (COVID-19). We compared cytokines in COVID-19 versus influenza to define differentiating features of the inflammatory response to these pathogens and their association with severe disease. Because elevated body mass index (BMI) is a known risk factor for severe COVID-19, we examined the relationship of BMI to cytokines associated with severe disease. METHODS Thirty-seven cytokines and chemokines were measured in plasma from 135 patients with COVID-19, 57 patients with influenza, and 30 healthy controls. Controlling for BMI, age, and sex, differences in cytokines between groups were determined by linear regression and random forest prediction was used to determine the cytokines most important in distinguishing severe COVID-19 and influenza. Mediation analysis was used to identify cytokines that mediate the effect of BMI and age on disease severity. RESULTS Interleukin-18 (IL-18), IL-1β, IL-6, and tumor necrosis factor-α (TNF-α) were significantly increased in COVID-19 versus influenza patients, whereas granulocyte macrophage colony-stimulating factor, interferon-γ (IFN-γ), IFN-λ1, IL-10, IL-15, and monocyte chemoattractant protein 2 were significantly elevated in the influenza group. In subgroup analysis based on disease severity, IL-18, IL-6, and TNF-α were elevated in severe COVID-19, but not in severe influenza. Random forest analysis identified high IL-6 and low IFN-λ1 levels as the most distinct between severe COVID-19 and severe influenza. Finally, IL-1RA was identified as a potential mediator of the effects of BMI on COVID-19 severity. CONCLUSIONS These findings point to activation of fundamentally different innate immune pathways in severe acute respiratory syndrome coronavirus 2 and influenza infection, and emphasize drivers of severe COVID-19 to focus both mechanistic and therapeutic investigations.
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Affiliation(s)
- Andrew H Karaba
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Weiqiang Zhou
- Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Leon L Hsieh
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Alexis Figueroa
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Guido Massaccesi
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Richard E Rothman
- Department of Emergency Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | | | - Lauren Sauer
- Department of Emergency Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Kathryn Shaw-Saliba
- Department of Emergency Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Paul W Blair
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Matthew L Robinson
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Sherry Leung
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Russell Wesson
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Nada Alachkar
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Ramy El-Diwany
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Hongkai Ji
- Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Andrea L Cox
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA
- Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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16
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Zakharchenko L, EL-Khuffash A, Hurley T, Kelly L, Melo A, Padden M, Franklin O, Molloy EJ. Infants with Down syndrome and congenital heart disease have altered peri-operative immune responses. Pediatr Res 2022; 92:1716-1723. [PMID: 35352006 PMCID: PMC9771806 DOI: 10.1038/s41390-022-02000-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 12/03/2021] [Accepted: 02/15/2022] [Indexed: 12/30/2022]
Abstract
BACKGROUND Infants with Down syndrome (DS) have an altered immune response. We aimed to characterise the inflammatory response in infants with DS and congenital heart disease (CHD) peri-operatively in comparison to infants with CHD and a normal chromosomal complement, and to healthy infants pre-operatively. METHODS Infants with DS/CHD, infants without DS but with CHD (CHD only) and healthy infants were prospectively recruited and serial serum cytokines evaluated peri-operatively using multiplex ELISA: tumour necrosis factor (TNF)-α and TNF-β; interferon (IFN)-γ, interleukin (IL)-1α, IL-2, IL-6, IL-8, IL-18, IL-1β, IL-10, and IL-1ra; vascular endothelial growth factor (VEGF); granulocyte macrophage colony-stimulating factor (GM-CSF); and erythropoietin (EPO). RESULTS Ninety-four infants were recruited including age-matched controls (n = 10), DS/CHD (n = 55), and CHD only (n = 29). Children with DS/CHD had significantly lower concentrations of several cytokines (IL-10, IL-6, IL-8, IL-1β, VEGF) in the pre- and post-operatively vs CHD only and controls. EPO and GM-CSF were significantly higher in DS/CHD (p value <0.05). CONCLUSIONS Children with DS/CHD had significantly lower concentrations of several cytokines compared to controls or children with CHD only. EPO and GM-CSF were significantly higher in children with DS/CHD. The assessment of the immune response may be suitable for the predictable clinical outcomes in these children. IMPACT This study demonstrated that children with Down syndrome (DS) and congenital heart disease (CHD) have significant alterations in pro-inflammatory and anti-inflammatory immune responses peri-operatively. These changes may contribute to adverse clinical outcomes, including sepsis, chylothorax, and autoimmunity. They may impact the pathogenesis and outcome post-operatively and long term in this population. Children with DS and CHD have significantly lower cytokine concentrations, increased EPO and GM-CSF, and decreased VEGF pre- and post-operatively. Assessing their inflammatory state peri-operatively may facilitate the development of a predictive model that can inform tailored management of these infants using novel therapies including immunomodulation.
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Affiliation(s)
- Lyudmyla Zakharchenko
- grid.417322.10000 0004 0516 3853Paediatric Cardiology, Children’s Health Ireland at Crumlin & Tallaght, Dublin, Ireland ,grid.452722.4National Children’s Research Centre, Crumlin, Dublin, Ireland
| | - Afif EL-Khuffash
- grid.452722.4National Children’s Research Centre, Crumlin, Dublin, Ireland ,grid.416068.d0000 0004 0617 7587Department of Neonatology, Rotunda Hospital, Dublin, Ireland ,grid.4912.e0000 0004 0488 7120Department of Paediatrics, Royal College of Surgeons in Ireland, Dublin, Ireland ,grid.8217.c0000 0004 1936 9705Paediatrics, Trinity College, The University of Dublin, Trinity Research in Childhood Centre (TRiCC) & Trinity Translational Medicine Institute (TTMI), Dublin, Ireland
| | - Tim Hurley
- grid.8217.c0000 0004 1936 9705Paediatrics, Trinity College, The University of Dublin, Trinity Research in Childhood Centre (TRiCC) & Trinity Translational Medicine Institute (TTMI), Dublin, Ireland
| | - Lynne Kelly
- grid.8217.c0000 0004 1936 9705Paediatrics, Trinity College, The University of Dublin, Trinity Research in Childhood Centre (TRiCC) & Trinity Translational Medicine Institute (TTMI), Dublin, Ireland
| | - Ashanti Melo
- grid.8217.c0000 0004 1936 9705Paediatrics, Trinity College, The University of Dublin, Trinity Research in Childhood Centre (TRiCC) & Trinity Translational Medicine Institute (TTMI), Dublin, Ireland
| | - Maureen Padden
- grid.452722.4National Children’s Research Centre, Crumlin, Dublin, Ireland
| | - Orla Franklin
- grid.417322.10000 0004 0516 3853Paediatric Cardiology, Children’s Health Ireland at Crumlin & Tallaght, Dublin, Ireland ,grid.452722.4National Children’s Research Centre, Crumlin, Dublin, Ireland ,grid.8217.c0000 0004 1936 9705Paediatrics, Trinity College, The University of Dublin, Trinity Research in Childhood Centre (TRiCC) & Trinity Translational Medicine Institute (TTMI), Dublin, Ireland ,grid.411886.20000 0004 0488 4333Paediatrics, Coombe Women and Infants University Hospital, Dublin, Ireland
| | - Eleanor J. Molloy
- grid.452722.4National Children’s Research Centre, Crumlin, Dublin, Ireland ,grid.4912.e0000 0004 0488 7120Department of Paediatrics, Royal College of Surgeons in Ireland, Dublin, Ireland ,grid.8217.c0000 0004 1936 9705Paediatrics, Trinity College, The University of Dublin, Trinity Research in Childhood Centre (TRiCC) & Trinity Translational Medicine Institute (TTMI), Dublin, Ireland ,grid.411886.20000 0004 0488 4333Paediatrics, Coombe Women and Infants University Hospital, Dublin, Ireland ,grid.417322.10000 0004 0516 3853Neonatology, Children’s Health Ireland at Crumlin & Tallaght, Dublin, Ireland
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Biological and Inflammatory Effects of Antigen 5 from Polybia paulista (Hymenoptera, Vespidae) Venom in Mouse Intraperitoneal Macrophages. Toxins (Basel) 2021; 13:toxins13120850. [PMID: 34941688 PMCID: PMC8703750 DOI: 10.3390/toxins13120850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 10/17/2021] [Accepted: 10/26/2021] [Indexed: 11/17/2022] Open
Abstract
The social wasp Polybia paulista (Hymenoptera, Vespidae) is highly aggressive, being responsible for many medical occurrences. One of the most allergenic components of this venom is Antigen 5 (Poly p 5). The possible modulation of the in vitro immune response induced by antigen 5 from P. paulista venom, expressed recombinantly (rPoly p 5), on BALB/c mice peritoneal macrophages, activated or not with LPS, was assessed. Here, we analyzed cell viability changes, expression of the phosphorylated form of p65 NF-κB subunit, nitric oxide (NO), proinflammatory cytokines production, and co-stimulatory molecules (CD80, CD86). The results suggest that rPoly p 5 does not affect NO production nor the expression of co-stimulatory molecules in mouse peritoneal macrophages. On the other hand, rPoly p 5 induced an increase in IL-1β production in non-activated macrophages and a reduction in the production of TNF-α and MCP-1 cytokines in activated macrophages. rPoly p 5 decreased the in vitro production of the phosphorylated p65 NF-κB subunit in non-activated macrophages. These findings suggest an essential role of this allergen in the polarization of functional M2 macrophage phenotypes, when analyzed in previously activated macrophages. Further investigations, mainly in in vivo studies, should be conducted to elucidate Polybia paulista Ag5 biological role in the macrophage functional profile modulation.
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Ghannam K, Zernicke J, Kedor C, Listing J, Burmester GR, Foell D, Feist E. Distinct Effects of Interleukin-1β Inhibition upon Cytokine Profile in Patients with Adult-Onset Still's Disease and Active Articular Manifestation Responding to Canakinumab. J Clin Med 2021; 10:jcm10194400. [PMID: 34640417 PMCID: PMC8509487 DOI: 10.3390/jcm10194400] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 09/13/2021] [Accepted: 09/21/2021] [Indexed: 11/16/2022] Open
Abstract
Adult-onset Still’s disease (AOSD) is a systemic auto-inflammatory disease characterized by the presence of immunologically mediated inflammation and deficient resolution of inflammation. Canakinumab is an approved IL-1β inhibitor in the treatment of AOSD with a balanced efficacy and safety profile. Since inflammatory cytokines play a major role in the pathogenesis of AOSD, we investigated the effects of canakinumab on the cytokine profile of AOSD patients from a randomized controlled trial. Multiplex analysis and ELISA were used to test the concentrations of several cytokines at three time points—week 0 (baseline), week 1 and week 4—in two patient groups—placebo and canakinumab. Two-way repeated-measures analysis of variance revealed a significant temporal effect on the concentrations of MRP 8/14, S100A12, IL-6 and IL-18 with a significant decrease at week 4 in the canakinumab group exclusively. Comparing responders with non-responders to canakinumab showed a significant decrease in MRP 8/14, IL-1RA, IL-18 and IL-6 in responders at week 4, while S100A12 levels decreased significantly in responders and non-responders. In summary, canakinumab showed a striking effect on the cytokine profile in patients with AOSD, exhibiting a clear association with clinical response.
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Affiliation(s)
- Khetam Ghannam
- Department of Rheumatology and Clinical Immunology, Charité—Universitätsmedizin Berlin, 10117 Berlin, Germany; (J.Z.); (C.K.); (G.-R.B.); (E.F.)
- Correspondence: ; Tel.: +49-(0)30-4505-13356; Fax: +49-(0)30-4505-13957
| | - Jan Zernicke
- Department of Rheumatology and Clinical Immunology, Charité—Universitätsmedizin Berlin, 10117 Berlin, Germany; (J.Z.); (C.K.); (G.-R.B.); (E.F.)
| | - Claudia Kedor
- Department of Rheumatology and Clinical Immunology, Charité—Universitätsmedizin Berlin, 10117 Berlin, Germany; (J.Z.); (C.K.); (G.-R.B.); (E.F.)
| | - Joachim Listing
- Epidemiology Unit, German Rheumatism Research Centre, 10117 Berlin, Germany;
| | - Gerd-R. Burmester
- Department of Rheumatology and Clinical Immunology, Charité—Universitätsmedizin Berlin, 10117 Berlin, Germany; (J.Z.); (C.K.); (G.-R.B.); (E.F.)
| | - Dirk Foell
- Pediatric Rheumatology and Immunology, University Hospital Muenster, 48149 Muenster, Germany;
| | - Eugen Feist
- Department of Rheumatology and Clinical Immunology, Charité—Universitätsmedizin Berlin, 10117 Berlin, Germany; (J.Z.); (C.K.); (G.-R.B.); (E.F.)
- Helios Department for Rheumatology Vogelsang-Gommern GmbH, 39245 Gommern, Germany
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Nazet U, Neubert P, Schatz V, Grässel S, Proff P, Jantsch J, Schröder A, Kirschneck C. Differential gene expression response of synovial fibroblasts from temporomandibular joints and knee joints to dynamic tensile stress. J Orofac Orthop 2021; 83:361-375. [PMID: 34142176 PMCID: PMC9596579 DOI: 10.1007/s00056-021-00309-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 04/18/2021] [Indexed: 12/17/2022]
Abstract
Purpose Apart from other risk factors, mechanical stress on joints can promote the development of osteoarthritis (OA), which can also affect the temporomandibular joint (TMJ), resulting in cartilage degeneration and synovitis. Synovial fibroblasts (SF) play an important role in upkeeping joint homeostasis and OA pathogenesis, but mechanical stress as a risk factor might act differently depending on the type of joint. We thus investigated the relative impact of mechanical stress on the gene expression pattern of SF from TMJs and knee joints to provide new insights into OA pathogenesis. Methods Primary SF isolated from TMJs and knee joints of mice were exposed to mechanical strain of varying magnitudes. Thereafter, the expression of marker genes of the extracellular matrix (ECM), inflammation and bone remodelling were analysed by quantitative real-time polymerase chain reaction (RT-qPCR). Results SF from the knee joints showed increased expression of genes associated with ECM remodelling, inflammation and bone remodelling after mechanical loading, whereas TMJ-derived SF showed reduced expression of genes associated with inflammation and bone remodelling. SF from the TMJ differed from knee-derived SF with regard to expression of ECM, inflammatory and osteoclastogenesis-promoting marker genes during mechanical strain. Conclusions Osteoarthritis-related ECM remodelling markers experience almost no changes in strain-induced gene expression, whereas inflammation and bone remodelling processes seem to differ depending on synovial fibroblast origin. Our data indicate that risk factors for the development and progression of osteoarthritis such as mechanical overuse have a different pathological impact in the TMJ compared to the knee joint. Supplementary Information The online version of this article (10.1007/s00056-021-00309-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ute Nazet
- Department of Orthodontics, University Medical Centre of Regensburg, Regensburg, Germany.
| | - Patrick Neubert
- Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg, Regensburg, Germany
| | - Valentin Schatz
- Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg, Regensburg, Germany
| | - Susanne Grässel
- Department of Orthopaedic Surgery, Experimental Orthopaedics, Centre for Medical Biotechnology, University of Regensburg, Regensburg, Germany
| | - Peter Proff
- Department of Orthodontics, University Medical Centre of Regensburg, Regensburg, Germany
| | - Jonathan Jantsch
- Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg, Regensburg, Germany
| | - Agnes Schröder
- Department of Orthodontics, University Medical Centre of Regensburg, Regensburg, Germany
| | - Christian Kirschneck
- Department of Orthodontics, University Medical Centre of Regensburg, Regensburg, Germany
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20
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Shams S, Martinez JM, Dawson JRD, Flores J, Gabriel M, Garcia G, Guevara A, Murray K, Pacifici N, Vargas MV, Voelker T, Hell JW, Ashouri JF. The Therapeutic Landscape of Rheumatoid Arthritis: Current State and Future Directions. Front Pharmacol 2021; 12:680043. [PMID: 34122106 PMCID: PMC8194305 DOI: 10.3389/fphar.2021.680043] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 05/05/2021] [Indexed: 12/14/2022] Open
Abstract
Rheumatoid arthritis (RA) is a debilitating autoimmune disease with grave physical, emotional and socioeconomic consequences. Despite advances in targeted biologic and pharmacologic interventions that have recently come to market, many patients with RA continue to have inadequate response to therapies, or intolerable side effects, with resultant progression of their disease. In this review, we detail multiple biomolecular pathways involved in RA disease pathogenesis to elucidate and highlight pathways that have been therapeutic targets in managing this systemic autoimmune disease. Here we present an up-to-date accounting of both emerging and approved pharmacological treatments for RA, detailing their discovery, mechanisms of action, efficacy, and limitations. Finally, we turn to the emerging fields of bioengineering and cell therapy to illuminate possible future targeted therapeutic options that combine material and biological sciences for localized therapeutic action with the potential to greatly reduce side effects seen in systemically applied treatment modalities.
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Affiliation(s)
- Shahin Shams
- Department of Biomedical Engineering, University of California, Davis, Davis, CA, United States
| | - Joseph M. Martinez
- Department of Pharmacology, University of California, Davis, Davis, CA, United States
| | - John R. D. Dawson
- Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA, United States
| | - Juan Flores
- Center for Neuroscience, University of California, Davis, Davis, CA, United States
| | - Marina Gabriel
- Department of Biomedical Engineering, University of California, Davis, Davis, CA, United States
| | - Gustavo Garcia
- Department of Biomedical Engineering, University of California, Davis, Davis, CA, United States
| | - Amanda Guevara
- Department of Pharmacology, University of California, Davis, Davis, CA, United States
| | - Kaitlin Murray
- Department of Anatomy, Physiology, and Cell Biology, University of California, Davis, Davis, CA, United States
| | - Noah Pacifici
- Department of Biomedical Engineering, University of California, Davis, Davis, CA, United States
| | | | - Taylor Voelker
- Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA, United States
| | - Johannes W. Hell
- Department of Pharmacology, University of California, Davis, Davis, CA, United States
| | - Judith F. Ashouri
- Rosalind Russell and Ephraim R. Engleman Rheumatology Research Center, Department of Medicine, University of California, San Francisco, CA, United States
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21
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Mortensen SB, Hansen ABE, Mogensen TH, Jakobsen MA, Beck HC, Harvald EB, Lambertsen KL, Johansen IS, Andersen DC. PYRIN inflammasome activation abrogates IL1Ra expression providing a new mechanism underlying FMF pathogenesis. Arthritis Rheumatol 2021; 73:2116-2126. [PMID: 33913256 DOI: 10.1002/art.41770] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 04/08/2021] [Indexed: 11/09/2022]
Abstract
OBJECTIVE Aberrant PYRIN inflammasome activity triggers FMF pathogenesis but the exact mechanism remains elusive and an obstacle to efficient treatment. Herein, we sought to identify PYRIN inflammasome specific mechanisms to improve FMF treatment and diagnostics in the future. METHODS PYRIN-specific protein secretion was assessed by proteome analysis in U937 derived macrophages, and specific findings were confirmed in PYRIN inflammasome activated monocytes from healthy blood donors (HD) and FMF patients, stratified by MEFV genotype categories corresponding to a suspected increasing FMF disease severity. RESULTS Proteome data revealed differential secretion pattern of IL1Rα from PYRIN and NLRP3 activated U937 derived macrophages, which was verified by ELISA and qPCR. Moreover, PYRIN activation significantly reduced IL1RN mRNA expression (p<0.001) and IL1Rα secretion (p<0.01) in healthy donor- and FMF monocytes, respectively. Independent of MEFV genotype, unstimulated FMF monocytes from colchicine treated patients secreted lower amounts of IL1Rα as compared to healthy donors (p<0.05) and displayed decreased ratios of IL1Rα/IL1β (p<0.05), suggesting a reduced anti-inflammatory capacity. CONCLUSION Our data show an inherent lack of IL-1 receptor antagonist expression specific to PYRIN inflammasome activation, providing a new mechanism underlying FMF pathogenesis. The reduced IL1Rα levels in FMF monocytes suggest a diminished anti-inflammatory capacity potentially leaving FMF patient monocytes more sensitive to pro-inflammatory stimuli, regardless of being in colchicine therapy. Thus, considering the potential clinical consequence of reduced monocyte IL1Rα secretion in FMF patients, we suggest further investigations into IL1Rα dynamics and its potential implications for FMF treatment in the future.
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Affiliation(s)
- Sussi B Mortensen
- Research Unit for Infectious Diseases, Odense University Hospital, University of Southern Denmark, Odense, 5000, Denmark.,Dept. of Clinical Research, University of Southern Denmark, Odense, 5000, Denmark.,Department of Clinical Immunology, Odense University Hospital, Odense, 5000, Denmark
| | - Ann-Brit E Hansen
- Dept. of Infectious Diseases, Copenhagen University Hospital, Hvidovre, 2650, Denmark
| | - Trine H Mogensen
- Dept. of Infectious Diseases, Aarhus University Hospital, Aarhus, 8000, Denmark.,Dept. of Biomedicine, Aarhus University, Aarhus, 8000, Denmark
| | - Marianne A Jakobsen
- Dept. of Clinical Research, University of Southern Denmark, Odense, 5000, Denmark.,Department of Clinical Immunology, Odense University Hospital, Odense, 5000, Denmark
| | - Hans C Beck
- Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, 5000, Denmark
| | - Eva B Harvald
- Dept. of Clinical Research, University of Southern Denmark, Odense, 5000, Denmark.,Laboratory of Molecular and Cellular Cardiology/Dept. of Clinical Biochemistry and Pharmacology; Odense University Hospital, Odense, 5000, Denmark
| | - Kate L Lambertsen
- Dept. of Neurobiology Research, Institute for Molecular Medicine, University of Southern Denmark, Odense, 5000, Denmark.,Dept. of Neurology, Odense University Hospital, Odense, 5000, Denmark
| | - Isik S Johansen
- Research Unit for Infectious Diseases, Odense University Hospital, University of Southern Denmark, Odense, 5000, Denmark.,Dept. of Clinical Research, University of Southern Denmark, Odense, 5000, Denmark
| | - Ditte C Andersen
- Dept. of Clinical Research, University of Southern Denmark, Odense, 5000, Denmark.,Laboratory of Molecular and Cellular Cardiology/Dept. of Clinical Biochemistry and Pharmacology; Odense University Hospital, Odense, 5000, Denmark
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22
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Pasin L, Cavalli G, Navalesi P, Sella N, Landoni G, Yavorovskiy AG, Likhvantsev VV, Zangrillo A, Dagna L, Monti G. Anakinra for patients with COVID-19: a meta-analysis of non-randomized cohort studies. Eur J Intern Med 2021; 86:34-40. [PMID: 33581979 PMCID: PMC7862887 DOI: 10.1016/j.ejim.2021.01.016] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 01/13/2021] [Accepted: 01/18/2021] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Severe COVID-19 cases have a detrimental hyper-inflammatory host response and different cytokine-blocking biologic agents were explored to improve outcomes. Anakinra blocks the activity of both IL-1α and IL‑1β and is approved for different autoinflammatory disorders, but it is used off-label for conditions characterized by an excess of cytokine production. Several studies on anakinra in COVID-19 patients reported positive effects. We performed a meta-analysis of all published evidence on the use of anakinra in COVID19 to investigate its effect on survival and need for mechanical ventilation. METHODS We searched for any study performed on adult patients with acute hypoxemic failure related to 2019-nCoV infection, receiving anakinra versus any comparator. Primary endpoint was mortality at the longest available follow-up. Adverse effects, need for mechanical ventilation and discharge at home with no limitations were also analysed. RESULTS Four observational studies involving 184 patients were included. Overall mortality of patients treated with anakinra was significantly lower than mortality in the control group (95% CI 0.14-0.48, p<0.0001). Moreover, patients treated with anakinra had a significantly lower risk of need for mechanical ventilation than controls (95% CI 0.250.74, p=0.002). No difference in adverse events and discharge at home with no limitations was observed. The Trial Sequential Analysis z-cumulative line reached the monitoring boundary for benefit and the required sample size. CONCLUSIONS Administration of anakinra in COVID-19 patients was safe and might be associated with reductions in both mortality and need for mechanical ventilation. Randomized clinical trials are warranted to confirm these findings.
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Affiliation(s)
- Laura Pasin
- Institute of Anesthesia and Intensive Care, Azienda Ospedaliera Universitaria di Padova, Padova (Italy)
| | - Giulio Cavalli
- Unit of Immunology, Rheumatology, Allergy, and Rare Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Paolo Navalesi
- Institute of Anesthesia and Intensive Care, Azienda Ospedaliera Universitaria di Padova, Padova (Italy); Department of Medicine (DIMED), University of Padova, Padova (Italy)
| | - Nicolò Sella
- Institute of Anesthesia and Intensive Care, Azienda Ospedaliera Universitaria di Padova, Padova (Italy)
| | - Giovanni Landoni
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan (Italy).
| | - Andrey G Yavorovskiy
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian
| | - Valery V Likhvantsev
- V. Negovsky Reanimatology Research Institute, Petrovka str, 25, b.2, Moscow, Russia; Department of Anesthesiology and Intensive Care, First Moscow State Medical University, Moscow, Russia
| | - Alberto Zangrillo
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan (Italy)
| | - Lorenzo Dagna
- Unit of Immunology, Rheumatology, Allergy, and Rare Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy; Faculty of Medicine, Vita-Salute San Raffaele University, Milan (Italy)
| | - Giacomo Monti
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan (Italy)
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23
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Martin P, Goldstein JD, Mermoud L, Diaz-Barreiro A, Palmer G. IL-1 Family Antagonists in Mouse and Human Skin Inflammation. Front Immunol 2021; 12:652846. [PMID: 33796114 PMCID: PMC8009184 DOI: 10.3389/fimmu.2021.652846] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 02/22/2021] [Indexed: 12/23/2022] Open
Abstract
Interleukin (IL)-1 family cytokines initiate inflammatory responses, and shape innate and adaptive immunity. They play important roles in host defense, but excessive immune activation can also lead to the development of chronic inflammatory diseases. Dysregulated IL-1 family signaling is observed in a variety of skin disorders. In particular, IL-1 family cytokines have been linked to the pathogenesis of psoriasis and atopic dermatitis. The biological activity of pro-inflammatory IL-1 family agonists is controlled by the natural receptor antagonists IL-1Ra and IL-36Ra, as well as by the regulatory cytokines IL-37 and IL-38. These four anti-inflammatory IL-1 family members are constitutively and highly expressed at steady state in the epidermis, where keratinocytes are a major producing cell type. In this review, we provide an overview of the current knowledge concerning their regulatory roles in skin biology and inflammation and their therapeutic potential in human inflammatory skin diseases. We further highlight some common misunderstandings and less well-known observations, which persist in the field despite recent extensive interest for these cytokines.
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Affiliation(s)
- Praxedis Martin
- Division of Rheumatology, Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Jérémie D. Goldstein
- Division of Rheumatology, Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Loïc Mermoud
- Division of Rheumatology, Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Alejandro Diaz-Barreiro
- Division of Rheumatology, Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Gaby Palmer
- Division of Rheumatology, Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
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24
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Cavalli G, Farina N, Campochiaro C, De Luca G, Della-Torre E, Tomelleri A, Dagna L. Repurposing of Biologic and Targeted Synthetic Anti-Rheumatic Drugs in COVID-19 and Hyper-Inflammation: A Comprehensive Review of Available and Emerging Evidence at the Peak of the Pandemic. Front Pharmacol 2020; 11:598308. [PMID: 33442386 PMCID: PMC7798432 DOI: 10.3389/fphar.2020.598308] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 11/17/2020] [Indexed: 12/15/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19) is a condition caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Severe cases of COVID-19 result in acute respiratory distress syndrome and death. A detrimental, hyper-inflammatory immune response with excess release of cytokines is the main driver of disease development and of tissue damage in these patients. Thus, repurposing of biologic agents and other pharmacological inhibitors of cytokines used for the treatment of various inflammatory conditions emerged as a logical therapeutic strategy to quench inflammation and improve the clinical outcome of COVID-19 patients. Evaluated agents include the interleukin one receptor blocker anakinra, monoclonal antibodies inhibiting IL-6 tocilizumab and sarilumab, monoclonal antibodies inhibiting granulocyte-monocyte colony stimulating factor and tumor necrosis factor, and Janus kinase inhibitors. In this review, we discuss the efficacy and safety of these therapeutic options based on direct personal experience and on published evidence from observational studies and randomized clinical trials.
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Affiliation(s)
- Giulio Cavalli
- Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Hospital, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Nicola Farina
- Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Hospital, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Corrado Campochiaro
- Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Hospital, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Giacomo De Luca
- Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Hospital, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Emanuel Della-Torre
- Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Hospital, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Alessandro Tomelleri
- Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Hospital, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Lorenzo Dagna
- Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Hospital, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
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25
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Wesley E, Uppendahl LD, Felices M, Dahl C, Messelt A, Boylan KLM, Skubitz APN, Vogel RI, Nelson HH, Geller MA. Cytomegalovirus and systemic inflammation at time of surgery is associated with worse outcomes in serous ovarian cancer. Gynecol Oncol 2020; 160:193-198. [PMID: 33168306 DOI: 10.1016/j.ygyno.2020.10.029] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 10/22/2020] [Indexed: 11/18/2022]
Abstract
OBJECTIVES Cytomegalovirus (CMV) is a common infection that establishes latency in healthy people. CMV has been associated with alterations of the immune compartment leading to improved responses, while inflammation has been shown to adversely impact outcomes. We investigated whether CMV serostatus predicts outcomes in ovarian cancer in the presence or absence of inflammation. METHODS A total of 106 patients with serous ovarian cancer from 2006 to 2009 were analyzed. CMV and systemic inflammation was measured using CMV immunoglobulin G (IgG) and C-reactive protein (CRP), respectively, in serum collected prior to cytoreduction. Patients were stratified by CMV IgG (non-reactive, reactive/borderline) and CRP (≤10, >10 mg/L) status. Overall survival (OS) and recurrence-free survival (RFS) were compared by group using log-rank tests and Cox proportional hazards regression models adjusting for age at surgery. RESULTS Of 106 eligible patients, 40 (37.7%) were CMV+/CRP+, 24 (22.6%) CMV+/CRP-, 19 (17.9%) CMV-/CRP+, and 23 (21.7%) CMV-/CRP-. CRP+ had higher CA-125 levels (P = 0.05) and higher rates of suboptimal debulking (P = 0.03). There were no other significant differences in demographic, surgical, or pathologic factors between groups. CMV+/CRP+ patients median RFS and OS were 16.9 months (95% CI: 9.0-21.1) and 31.7 months (95% CI: 25.0-48.7), respectively, with a significantly worse RFS (aHR: 1.85, 95% CI: 1.05-3.24, P = 0.03) and OS (aHR: 2.12, 95% CI: 1.17-3.82, P = 0.01) compared to CMV-/CRP- (RFS = 31.2 months (95% CI: 16.0-56.4) and OS = 63.8 months (95% CI: 50.7-87.0)). CMV+/CRP- group displayed the longest OS (89.3 months). CONCLUSIONS Previous exposure to CMV and high CRP at surgery portended worse RFS and OS compared to women who tested negative. The CMV+/CRP- group had the longest OS, indicating that CMV status alone, in the absence of inflammation, may be protective.
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Affiliation(s)
- Erin Wesley
- Department of Obstetrics, Gynecology, and Women's Health, University of Minnesota, Minneapolis, MN, United States
| | - Locke D Uppendahl
- Department of Obstetrics, Gynecology, and Women's Health, University of Minnesota, Minneapolis, MN, United States
| | - Martin Felices
- Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN, United States; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States
| | - Carly Dahl
- Department of Obstetrics, Gynecology, and Women's Health, University of Minnesota, Minneapolis, MN, United States
| | - Audrey Messelt
- Department of Obstetrics, Gynecology, and Women's Health, University of Minnesota, Minneapolis, MN, United States
| | - Kristin L M Boylan
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, United States
| | - Amy P N Skubitz
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, United States
| | - Rachel I Vogel
- Department of Obstetrics, Gynecology, and Women's Health, University of Minnesota, Minneapolis, MN, United States; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States
| | - Heather H Nelson
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States; Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, United States
| | - Melissa A Geller
- Department of Obstetrics, Gynecology, and Women's Health, University of Minnesota, Minneapolis, MN, United States; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States.
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26
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Goelz N, Bosch AMS, Rand ML, Eekels JJM, Franzoso FD, Schmugge M. Increased levels of IL-10 and IL-1Ra counterbalance the proinflammatory cytokine pattern in acute pediatric immune thrombocytopenia. Cytokine 2020; 130:155078. [PMID: 32220726 DOI: 10.1016/j.cyto.2020.155078] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 03/17/2020] [Accepted: 03/18/2020] [Indexed: 12/12/2022]
Abstract
Immune thrombocytopenia (ITP) is an autoimmune disease which leads to accelerated platelet clearance. We investigated the plasma cytokine, chemokine and growth factor signatures and their clinical significance in pediatric ITP patients during acute, chronic and follow-up stages as well as the effects of intravenous immunoglobulin (IVIg) treatment, by using the Multiplex technology. In acute ITP before and/or after IVIg treatment we found significantly increased plasma levels of the pro- (tumour necrosis factor-α (TNF-α), interleukin IL-15) and anti- (IL-1 receptor antagonist (Ra), IL-10 and the growth factor interferon γ-induced protein (IP-10)) inflammatory cytokines, compared to healthy controls. Except for IL1-Ra, these cytokines decreased to normal levels in chronic patients. In contrast, growth-regulated α protein (GRO) and soluble CD40 ligand (sCD40L), known as platelet-derived molecules, were found to be significantly decreased in acute and increased in chronic ITP patients compared to healthy controls. GRO levels positively correlated with the platelet counts in the follow-up and chronic cohort. Monocyte counts showed a significant positive correlation only with IP-10 levels in acute ITP after IVIg treatment and follow-up patients. Expression levels of mRNAs for macrophage inflammatory protein MIP1-β, IL-1Ra and GRO determined in peripheral blood mononuclear cells (PBMCs) were significantly reduced in both acute and chronic ITP compared to controls. Our findings suggest that the different clinical presentation of acute and chronic pediatric ITP and to a lesser extent the IVIg treatment effects are characterized overall by a counterbalanced cytokine, chemokine and growth factor pattern response that might exert a pathogenic role in this disease.
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Affiliation(s)
- Nadine Goelz
- Division of Hematology and Children's Research Center, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032 Zurich, Switzerland
| | - Alessandra M S Bosch
- Division of Hematology and Children's Research Center, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032 Zurich, Switzerland
| | - Margaret L Rand
- Division of Hematology/Oncology, Translational Medicine, Research Institute, Hospital for Sick Children, Departments of Laboratory Medicine & Pathobiology, Biochemistry, and Pediatrics, University of Toronto, 555 University Avenue, Toronto M5G 1X8, Canada
| | - Julia J M Eekels
- Department of Immunology and Transfusion Medicine, University Hospital Greifswald, F-Sauerbruch-Strasse, 17475 Greifswald, Germany
| | - Francesca D Franzoso
- Division of Hematology and Children's Research Center, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032 Zurich, Switzerland
| | - Markus Schmugge
- Division of Hematology and Children's Research Center, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032 Zurich, Switzerland.
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27
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Gavrilovic S, Andrijevic A, Mujakovic A, Odeyemi Y, Paralija B, Gajic O. Adjunct corticosteroid treatment in patients with pneumonia: A precision medicine approach. Bosn J Basic Med Sci 2019; 19:315-320. [PMID: 30640592 PMCID: PMC6868487 DOI: 10.17305/bjbms.2019.3977] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Accepted: 12/18/2018] [Indexed: 01/29/2023] Open
Abstract
Pneumonia is the leading infectious cause of death worldwide. While inflammation is critically important in host response to microbial invasion, exaggerated inflammation can damage the lungs, contributing to respiratory failure and mortality. Corticosteroids are effective in reducing inflammation and can also cause immune suppression. Presently, clinicians are unable to reliably distinguish between exaggerated and appropriate immune response and thus cannot rapidly identify patients most likely to benefit from adjunctive corticosteroids. In this review, we propose a biomarker-guided, precision medicine approach to corticosteroid treatment, aimed to give these medications at appropriate dose and time and only to patients who have exaggerated inflammation.
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Affiliation(s)
- Srdjan Gavrilovic
- Intensive Care Unit, Institute for Pulmonary Diseases of Vojvodina, Sremska Kamenica, Serbia Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia.
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28
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Barbier L, Ferhat M, Salamé E, Robin A, Herbelin A, Gombert JM, Silvain C, Barbarin A. Interleukin-1 Family Cytokines: Keystones in Liver Inflammatory Diseases. Front Immunol 2019; 10:2014. [PMID: 31507607 PMCID: PMC6718562 DOI: 10.3389/fimmu.2019.02014] [Citation(s) in RCA: 102] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Accepted: 08/08/2019] [Indexed: 12/12/2022] Open
Abstract
The pyrogenic property being the first activity described, members of the interleukin-1 superfamily (IL-1α, IL-1β, IL-18, and the newest members: IL-33, IL-36, IL-37, and IL-38) are now known to be involved in several inflammatory diseases such as obesity, atherosclerosis, cancer, viral and parasite infections, and auto-inflammatory syndromes as well as liver diseases. Inflammation processes are keystones of chronic liver diseases, of which the etiology may be viral or toxic, as in alcoholic or non-alcoholic liver diseases. Inflammation is also at stake in acute liver failure involving massive necrosis, and in ischemia-reperfusion injury in the setting of liver transplantation. The role of the IL-1 superfamily of cytokines and receptors in liver diseases can be either protective or pro-inflammatory, depending on timing and the environment. Our review provides an overview of current understanding of the IL-1 family members in liver inflammation, highlighting recent key investigations, and therapeutic perspectives. We have tried to apply the concept of trained immunity to liver diseases, based on the role of the members of the IL-1 superfamily, first of all IL-1β but also IL-18 and IL-33, in modulating innate lymphoid immunity carried by natural killer cells, innate lymphoid cells or innate T-αβ lymphocytes.
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Affiliation(s)
- Louise Barbier
- INSERM U1082, Poitiers, France.,Department of Digestive Surgery and Liver Transplantation, Trousseau University Hospital, Tours University, Tours, France
| | | | - Ephrem Salamé
- INSERM U1082, Poitiers, France.,Department of Digestive Surgery and Liver Transplantation, Trousseau University Hospital, Tours University, Tours, France
| | - Aurélie Robin
- INSERM U1082, Poitiers University Hospital, Poitiers, France
| | | | - Jean-Marc Gombert
- INSERM U1082, Poitiers, France.,Department of Immunology and Inflammation, Poitiers University Hospital, University of Poitiers, Poitiers, France
| | - Christine Silvain
- Department of Hepatology and Gastroenterology, Poitiers University Hospital, University of Poitiers, Poitiers, France
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Tsai CF, Chen JH, Yeh WL. Pulmonary fibroblasts-secreted CXCL10 polarizes alveolar macrophages under pro-inflammatory stimuli. Toxicol Appl Pharmacol 2019; 380:114698. [PMID: 31394157 DOI: 10.1016/j.taap.2019.114698] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 08/01/2019] [Accepted: 08/03/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND During acute lung injury, lung fibroblasts produce chemokines that assist the activation and migration of resident macrophages. The interactions between pulmonary fibroblasts and alveolar macrophages demonstrate the early event in the recruitment of immune cells, and the production of chemokines appear to be central mediators of the initiation and progression of inflammatory responses. In this study, the aim was to investigate the signaling pathway leading to CXCL10 secretion and the effects of CXCL10 released by activated fibroblasts on regulating macrophage polarization in a pro-inflammatory microenvironment. METHODS The expression of chemokines CCL2, CCL5, CXCL10, and CXCL12, and the phosphorylation of signaling molecules STAT3, FAK, GSK3αβ and PKCδ were investigated by real time-PCR, ELISA, or Western blot on TNFα- or IL-1β-activated MRC-5 pulmonary fibroblasts. By collecting conditioned medium from TNFα-activated fibroblasts, the expression of iNOS and arginase I on MH-S alveolar macrophages were examined by real-time PCR. Surface markers CD86 and CD206 expressions on alveolar macrophages were also evaluated by flow cytometry. RESULTS We found that CXCL10 production was significantly elevated on MRC-5 fibroblasts under TNFα- or IL-1β treatment. In addition, we revealed that TNFα and IL-1β initiated phosphorylation of STAT3, FAK, GSK3αβ and PKCδ signaling cascade, leading to the elevation of CXCL10 expression. Moreover, conditioned medium collected from TNFα-activated MRC-5 fibroblasts increased iNOS and CD86 expressions and decreased arginase I and CD206 expressions on MH-S alveolar macrophages, and neutralization of CXCL10 abolished these observed phenomena. CONCLUSION These results suggest that CXCL10 is crucial in activated fibroblasts-promoted M1 phenotype polarization of alveolar macrophages. In this regard, targeting fibroblasts-released CXCL10 may be promising as anti-inflammatory therapy against acute lung injury.
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Affiliation(s)
- Cheng-Fang Tsai
- Department of Biotechnology, Asia University, No.500 Lioufeng Road, Taichung 41354, Taiwan
| | - Jia-Hong Chen
- Department of General Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 42743, Taiwan
| | - Wei-Lan Yeh
- Institute of New Drug Development, China Medical University, No.91 Hsueh-Shih Road, Taichung 40402, Taiwan.
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Lambertsen KL, Finsen B, Clausen BH. Post-stroke inflammation-target or tool for therapy? Acta Neuropathol 2019; 137:693-714. [PMID: 30483945 PMCID: PMC6482288 DOI: 10.1007/s00401-018-1930-z] [Citation(s) in RCA: 304] [Impact Index Per Article: 50.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 11/03/2018] [Accepted: 11/04/2018] [Indexed: 12/22/2022]
Abstract
Inflammation is currently considered a prime target for the development of new stroke therapies. In the acute phase of ischemic stroke, microglia are activated and then circulating immune cells invade the peri-infarct and infarct core. Resident and infiltrating cells together orchestrate the post-stroke inflammatory response, communicating with each other and the ischemic neurons, through soluble and membrane-bound signaling molecules, including cytokines. Inflammation can be both detrimental and beneficial at particular stages after a stroke. While it can contribute to expansion of the infarct, it is also responsible for infarct resolution, and influences remodeling and repair. Several pre-clinical and clinical proof-of-concept studies have suggested the effectiveness of pharmacological interventions that target inflammation post-stroke. Experimental evidence shows that targeting certain inflammatory cytokines, such as tumor necrosis factor, interleukin (IL)-1, IL-6, and IL-10, holds promise. However, as these cytokines possess non-redundant protective and immunoregulatory functions, their neutralization or augmentation carries a risk of unwanted side effects, and clinical translation is, therefore, challenging. This review summarizes the cell biology of the post-stroke inflammatory response and discusses pharmacological interventions targeting inflammation in the acute phase after a stroke that may be used alone or in combination with recanalization therapies. Development of next-generation immune therapies should ideally aim at selectively neutralizing pathogenic immune signaling, enhancing tissue preservation, promoting neurological recovery and leaving normal function intact.
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Affiliation(s)
- Kate Lykke Lambertsen
- Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000, Odense, Denmark.
- Department of Clinical Research, BRIDGE-Brain Research-Inter-Disciplinary Guided Excellence, University of Southern Denmark, 5000, Odense C, Denmark.
- Department of Neurology, Odense University Hospital, 5000, Odense, Denmark.
| | - Bente Finsen
- Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000, Odense, Denmark
- Department of Clinical Research, BRIDGE-Brain Research-Inter-Disciplinary Guided Excellence, University of Southern Denmark, 5000, Odense C, Denmark
| | - Bettina Hjelm Clausen
- Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000, Odense, Denmark
- Department of Clinical Research, BRIDGE-Brain Research-Inter-Disciplinary Guided Excellence, University of Southern Denmark, 5000, Odense C, Denmark
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Metformin induces the AP-1 transcription factor network in normal dermal fibroblasts. Sci Rep 2019; 9:5369. [PMID: 30926854 PMCID: PMC6441003 DOI: 10.1038/s41598-019-41839-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2018] [Accepted: 03/18/2019] [Indexed: 12/21/2022] Open
Abstract
Metformin is a widely-used treatment for type 2 diabetes and is reported to extend health and lifespan as a caloric restriction (CR) mimetic. Although the benefits of metformin are well documented, the impact of this compound on the function and organization of the genome in normal tissues is unclear. To explore this impact, primary human fibroblasts were treated in culture with metformin resulting in a significant decrease in cell proliferation without evidence of cell death. Furthermore, metformin induced repositioning of chromosomes 10 and 18 within the nuclear volume indicating altered genome organization. Transcriptome analyses from RNA sequencing datasets revealed that alteration in growth profiles and chromosome positioning occurred concomitantly with changes in gene expression profiles. We further identified that different concentrations of metformin induced different transcript profiles; however, significant enrichment in the activator protein 1 (AP-1) transcription factor network was common between the different treatments. Comparative analyses revealed that metformin induced divergent changes in the transcriptome than that of rapamycin, another proposed mimetic of CR. Promoter analysis and chromatin immunoprecipitation assays of genes that changed expression in response to metformin revealed enrichment of the transcriptional regulator forkhead box O3a (FOXO3a) in normal human fibroblasts, but not of the predicted serum response factor (SRF). Therefore, we have demonstrated that metformin has significant impacts on genome organization and function in normal human fibroblasts, different from those of rapamycin, with FOXO3a likely playing a role in this response.
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Interleukin-1 Receptor Antagonist Modulates Liver Inflammation and Fibrosis in Mice in a Model-Dependent Manner. Int J Mol Sci 2019; 20:ijms20061295. [PMID: 30875826 PMCID: PMC6471711 DOI: 10.3390/ijms20061295] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 03/04/2019] [Accepted: 03/06/2019] [Indexed: 12/19/2022] Open
Abstract
Background: Interleukin-1 (IL-1)β and IL-1 receptor antagonist (IL-1Ra) have been proposed as important mediators during chronic liver diseases. We aimed to determine whether the modulation of IL-1β signaling with IL-1Ra impacts on liver fibrosis. Methods: We assessed the effects of IL-1β on human hepatic stellate cells (HSC) and in mouse models of liver fibrosis induced by bile duct ligation (BDL) or carbon tetrachloride treatment (CCl-4). Results: Human HSCs treated with IL-1β had increased IL-1β, IL-1Ra, and MMP-9 expressions in vitro. HSCs treated with IL-1β had reduced α-smooth muscle actin expression. These effects were all prevented by IL-1Ra treatment. In the BDL model, liver fibrosis and Kuppfer cell numbers were increased in IL-1Ra KO mice compared to wild type mice and wild type mice treated with IL-1Ra. In contrast, after CCl-4 treatment, fibrosis, HSC and Kupffer cell numbers were decreased in IL-1Ra KO mice compared to the other groups. IL-1Ra treatment provided a modest protective effect in the BDL model and was pro-fibrotic in the CCl-4 model. Conclusions: We demonstrated bivalent effects of IL-1Ra during liver fibrosis in mice. IL-1Ra was detrimental in the CCl-4 model, whereas it was protective in the BDL model. Altogether these data suggest that blocking IL-1-mediated inflammation may be beneficial only in selective liver fibrotic disease.
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Rütten S, Schrödl W, Abraham G. Modulation of TNF-α, IL-1Ra and IFN-γ in equine whole blood culture by glucocorticoids. Vet Immunol Immunopathol 2019; 210:1-5. [PMID: 30947974 DOI: 10.1016/j.vetimm.2019.03.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Revised: 02/26/2019] [Accepted: 03/03/2019] [Indexed: 11/30/2022]
Abstract
Glucocorticoids are important drugs in the treatment of many inflammatory, autoimmune and allergic diseases in humans and animals. We investigated the effects of hydrocortisone and dexamethasone on TNF-α, IL-1Ra and INF-γ release in stimulated whole blood cell culture from healthy horses. Whole blood cell cultures proved to be useful for the characterization of the anti-inflammatory properties of new drugs. Diluted equine whole blood was exposed to lipopolysaccharide (LPS) and PCPwL (a cocktail consisting of phythemagglutinin E, concanavalin A, pokeweed mitogen and lipopolysaccharide) in the presence or absence of hydrocortisone and dexamethasone (10-12 - 10-5 M). TNF-α and IL-1Ra (LPS) as well as IFN-γ (PCPwL) levels were measured in the supernatants using specific enzyme-linked immunosorbent assay (ELISA). The LPS-induced TNF-α and IL-1Ra as well as the PCPwL-induced IFN-γ levels were more potently suppressed by dexamethasone than by hydrocortisone in a concentration-dependent manner. Dexamethasone inhibited TNF-α, IL-1Ra and IFN-γ with the half maximal inhibition concentration (IC50) values of 0.09 μM, 0.453 μM and 0.001 μM, respectively, whereas hydrocortisone inhibited these cytokines with lower IC50 values of 1.45 μM, 2.96 μM and 0.09 μM, respectively. Our results suggest that the equine whole blood test system is useful and reliable to evaluate drug effects and immunological alterations and offers several advantages including simple and cheap performance in physiological and pathological conditions.
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Affiliation(s)
- Simon Rütten
- Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, An den Tierkliniken 15, 04103 Leipzig, Germany
| | - Wieland Schrödl
- Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, An den Tierkliniken 15, 04103 Leipzig, Germany; Institute of Bacteriology und Mycology, University of Leipzig, 04103 Leipzig, Germany
| | - Getu Abraham
- Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, An den Tierkliniken 15, 04103 Leipzig, Germany.
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McPhillips L, Kholwadwala D, Sison CP, Gruber D, Ojamaa K. A Novel Brain Injury Biomarker Correlates with Cyanosis in Infants with Congenital Heart Disease. Pediatr Cardiol 2019; 40:546-553. [PMID: 30430186 DOI: 10.1007/s00246-018-2023-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 11/01/2018] [Indexed: 12/22/2022]
Abstract
Cyanotic heart lesions are a complex subset of congenital heart disease (CHD) in which patients are desaturated until surgical repair or palliation. We hypothesized that a direct relationship would exist between degree of desaturation and presence of systemic inflammation and brain injury in unrepaired patients less than 1 year of age. The pre-operative desaturation with augmented systemic inflammation would predict a more complex post-operative course. Fifty patients with CHD were enrolled in this study and classified as cyanotic (O2 ≤ 90%) or acyanotic (O2 > 90%) based on SpO2. Serum inflammatory mediators measured included interleukins (IL)-6, IL-8, IL-12p70, IL-10, IL-1β, tumor necrosis factor (TNF)-α, interferon (INF)-γ; macrophage inhibitory factor (MIF) and a novel brain biomarker, phosphorylated neurofilament heavy subunit (pNF-H). Twenty-two cyanotic and 28 acyanotic subjects were enrolled with SpO2 of 78 ± 18% and 98 ± 2% (p < 0.001), respectively, and mean age of 72 days (range 2-303) and 102 days (range 1-274), respectively. Cyanotic vs acyanotic subjects had elevated serum IL-6 (6.6 ± 7.6 vs 2.9 ± 2.9 pg/ml, p = 0.019) and pNF-H (222 ± 637 vs 57 ± 121 pg/ml, p = 0.046), and both biomarkers correlated with degree of desaturation (Spearman rank-order correlation ρ = - 0.30, p = 0.037 and ρ = - 0.29 p = 0.049, respectively). Post-operative inotrope scores at 24 h and duration of mechanical ventilation correlated inversely with pre-operative oxygen saturation (ρ = - 0.380, p = 0.014 and ρ = - 0.362, p = 0.020, respectively). The degree of pre-operative desaturation correlated with a more complicated post-operative course supporting the need for advanced peri-operative therapy in this population.
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Affiliation(s)
- Lindsey McPhillips
- Division of Pediatric Cardiology, Department of Pediatrics, Cohen Children's Medical Center of New York at Northwell Health, New Hyde Park, NY, 11040, USA. .,Barbara and Donald Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, 11549, USA.
| | - Dipak Kholwadwala
- Division of Pediatric Cardiology, Department of Pediatrics, Cohen Children's Medical Center of New York at Northwell Health, New Hyde Park, NY, 11040, USA.,Barbara and Donald Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, 11549, USA
| | - Cristina P Sison
- Barbara and Donald Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, 11549, USA.,Biostatistics Unit, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, 11030, USA
| | - Dorota Gruber
- Division of Pediatric Cardiology, Department of Pediatrics, Cohen Children's Medical Center of New York at Northwell Health, New Hyde Park, NY, 11040, USA.,Barbara and Donald Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, 11549, USA
| | - Kaie Ojamaa
- Division of Pediatric Cardiology, Department of Pediatrics, Cohen Children's Medical Center of New York at Northwell Health, New Hyde Park, NY, 11040, USA. .,Barbara and Donald Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, 11549, USA. .,Department of Biomedical Sciences, New York Institute of Technology College of Osteopathic Medicine, Old Westbury, NY, 11568, USA.
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35
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Wang W, Liu Y, Guo J, He H, Mi X, Chen C, Xie J, Wang S, Wu P, Cao F, Bai L, Si Q, Xiang R, Luo Y. miR-100 maintains phenotype of tumor-associated macrophages by targeting mTOR to promote tumor metastasis via Stat5a/IL-1ra pathway in mouse breast cancer. Oncogenesis 2018; 7:97. [PMID: 30563983 PMCID: PMC6299090 DOI: 10.1038/s41389-018-0106-y] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 10/09/2018] [Accepted: 11/26/2018] [Indexed: 01/10/2023] Open
Abstract
Tumor-associated macrophages (TAMs), the main part of immune cells in tumor microenvironment (TME), play a potent role in promoting tumorigenesis through mechanisms such as stimulating angiogenesis, enhancing tumor migration and suppressing antitumor immunity. MicroRNAs (miRNAs) are considered as crucial regulators in multiple biological processes. The relationship between miRNAs and macrophages function has been extensively reported, but the roles that miRNAs play in regulating TAMs phenotype remain unclear. In this study, we screened highly expressed microRNAs in TAMs, and first identified that miR-100 represented a TAMs-high expression pattern and maintained TAMs phenotype by targeting mTOR signaling pathway. Moreover, miR-100 expression level in TAMs was positively related to IL-1ra secretion, a traditional immune-suppressive cytokine, which was determined to promote tumor cells stemness via stimulating Hedgehog pathway. Mechanism study suggested that mTOR/Stat5a pathway was involved in IL-1ra transcriptional regulation process mediated by miR-100. More importantly, tumor metastasis and invasion capacity were significantly decreased in a 4T1 mouse breast cancer model injected intratumorally with miR-100 antagomir, and combination therapy with cisplatin showed much better benefit. In this study, we confirm that highly expressed miR-100 maintains the phenotype of TAMs and promotes tumor metastasis via enhancing IL-1ra secretion. Interfering miR-100 expression of TAMs in mouse breast cancer model could inhibit TAMs pro-tumor function and reduce tumor metastasis, which suggests that miR-100 could serve as a potential therapy target to remodel tumor microenvironment in breast cancer.
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Affiliation(s)
- Wei Wang
- Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 100005, Beijing, China.,Collaborative Innovation Center for Biotherapy, School of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 100005, Beijing, China
| | - Yan Liu
- Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 100005, Beijing, China.,Collaborative Innovation Center for Biotherapy, School of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 100005, Beijing, China
| | - Jian Guo
- Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 100005, Beijing, China.,Collaborative Innovation Center for Biotherapy, School of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 100005, Beijing, China
| | - Huiwen He
- Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 100005, Beijing, China.,Collaborative Innovation Center for Biotherapy, School of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 100005, Beijing, China
| | - Xue Mi
- Department of Immunology, Medical School of Nankai University, 300071, Tianjin, China
| | - Chong Chen
- Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 100005, Beijing, China.,Collaborative Innovation Center for Biotherapy, School of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 100005, Beijing, China
| | - Junling Xie
- Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 100005, Beijing, China.,Collaborative Innovation Center for Biotherapy, School of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 100005, Beijing, China
| | - Shengnan Wang
- Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 100005, Beijing, China.,Collaborative Innovation Center for Biotherapy, School of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 100005, Beijing, China
| | - Peng Wu
- Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 100005, Beijing, China.,Collaborative Innovation Center for Biotherapy, School of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 100005, Beijing, China
| | - Fengqi Cao
- Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 100005, Beijing, China.,Collaborative Innovation Center for Biotherapy, School of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 100005, Beijing, China
| | - Lipeng Bai
- Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 100005, Beijing, China.,Collaborative Innovation Center for Biotherapy, School of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 100005, Beijing, China
| | - Qin Si
- Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 100005, Beijing, China.,Collaborative Innovation Center for Biotherapy, School of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 100005, Beijing, China
| | - Rong Xiang
- Department of Immunology, Medical School of Nankai University, 300071, Tianjin, China
| | - Yunping Luo
- Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 100005, Beijing, China. .,Collaborative Innovation Center for Biotherapy, School of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 100005, Beijing, China.
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Alipour S, Sakhinia E, Khabbazi A, Samadi N, Babaloo Z, Azad M, Abolhasani S, Farhadi J, Jadideslam G, Roshanravan N, Nouri M. Methylation status of interleukin-6 gene promoter in patients with Behçet's disease. ACTA ACUST UNITED AC 2018; 16:229-234. [PMID: 30076035 DOI: 10.1016/j.reuma.2018.06.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 05/07/2018] [Accepted: 06/22/2018] [Indexed: 11/19/2022]
Abstract
BACKGROUND IL-6 mRNA expression is significantly high in many autoimmune diseases such as Behçet's disease; this is often related with more aggressive phenotypes. Nevertheless, the essential molecular process for its high expression has not been completely realized. The aim of this study was undertaken to estimate the gene copy number variation and promoter methylation to IL-6's high expression. METHODS This study was performed on 51 patients and 61 healthy controls. Initially, DNA and RNA were extracted from all specimens. Promoter methylation levels of IL-6 were evaluated by MeDIP-qPCR technique. Also, IL-6 gene expression was measured by Real-time PCR. After that, we evaluated the relationship between gene expression and methylation, as well as their relationship with clinical specification. RESULTS As we expected, the expression level of IL-6 gene increased significantly in the patient group compared to the healthy subjects. Also, the relative promoter methylation level of the IL-6 mRNA was significantly lower in patient group compared to healthy group (p<0.001). DISCUSSION We disclosed that the promoter hypomethylation may be considered as one of the main defects for IL-6 mRNA high expression in patients with Behçet's disease.
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Affiliation(s)
- Shahriar Alipour
- Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Iran; Connective Tissue Diseases Research Center, Tabriz University of Medical Science, Iran
| | - Ebrahim Sakhinia
- Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alireza Khabbazi
- Connective Tissue Diseases Research Center, Tabriz University of Medical Science, Iran
| | - Nasser Samadi
- Cancer Biochemistry, Cancer Biotechnology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zohreh Babaloo
- Department of Immunology Medicine Faculty, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahdi Azad
- Department of Medical Laboratory Sciences, Faculty of Allied Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Somayeh Abolhasani
- Faculty of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Jafar Farhadi
- Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Iran; Connective Tissue Diseases Research Center, Tabriz University of Medical Science, Iran
| | - Golamreza Jadideslam
- Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Iran; Connective Tissue Diseases Research Center, Tabriz University of Medical Science, Iran
| | - Neda Roshanravan
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Nouri
- Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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Oh SH, Choi C, Noh JE, Lee N, Jeong YW, Jeon I, Shin JM, Kim JH, Kim HJ, Lee JM, Kim HS, Kim OJ, Song J. Interleukin-1 receptor antagonist-mediated neuroprotection by umbilical cord-derived mesenchymal stromal cells following transplantation into a rodent stroke model. Exp Mol Med 2018; 50:1-12. [PMID: 29650950 PMCID: PMC5938060 DOI: 10.1038/s12276-018-0041-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Accepted: 12/21/2017] [Indexed: 01/01/2023] Open
Abstract
The human umbilical cord is a promising source of mesenchymal stromal cells (MSCs). Intravenous administration of human umbilical cord-derived MSCs (IV-hUMSCs) showed a favorable effect in a rodent stroke model by a paracrine mechanism. However, its underlying therapeutic mechanisms must be determined for clinical application. We investigated the therapeutic effects and mechanisms of our good manufacturing practice (GMP)-manufactured hUMSCs using various cell doses and delivery time points in a rodent model of stroke. IV-hUMSCs at a dose of 1 × 106 cells at 24 h after stroke improved functional deficits and reduced neuronal damage by attenuation of post-ischemic inflammation. Transcriptome and immunohistochemical analyses showed that interleukin-1 receptor antagonist (IL-1ra) was highly upregulated in ED-1-positive inflammatory cells in rats treated with IV-hUMSCs. Treatment with conditioned medium of hUMSCs increased the expression of IL-1ra in a macrophage cell line via activation of cAMP-response element-binding protein (CREB). These results strongly suggest that the attenuation of neuroinflammation mediated by endogenous IL-1ra is an important therapeutic mechanism of IV-hUMSCs for the treatment of stroke.
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Affiliation(s)
- Seung-Hun Oh
- Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Chunggab Choi
- Department of Biomedical Science, CHA University, Seongnam, Republic of Korea
| | - Jeong-Eun Noh
- Department of Biomedical Science, CHA University, Seongnam, Republic of Korea
| | - Nayeon Lee
- Department of Biomedical Science, CHA University, Seongnam, Republic of Korea
| | - Yong-Woo Jeong
- Department of Biomedical Science, CHA University, Seongnam, Republic of Korea
| | - Iksoo Jeon
- Department of Biomedical Science, CHA University, Seongnam, Republic of Korea
| | - Jeong-Min Shin
- Development Division, CHA Biotech, Co. Ltd., Seongnam, Republic of Korea.,Department of Biotechnology, CHA University, Seongnam, Republic of Korea
| | - Ji-Hye Kim
- Development Division, CHA Biotech, Co. Ltd., Seongnam, Republic of Korea
| | - Ho-Jin Kim
- Development Division, CHA Biotech, Co. Ltd., Seongnam, Republic of Korea
| | - Ji-Min Lee
- Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Hyun-Sook Kim
- Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Ok-Joon Kim
- Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea.
| | - Jihwan Song
- Department of Biomedical Science, CHA University, Seongnam, Republic of Korea. .,CHA Stem Cell Institute, CHA University, Seongnam, Republic of Korea.
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van der Heiden M, Berbers GAM, Fuentes S, van Zelm MC, Boots AMH, Buisman AM. An Explorative Biomarker Study for Vaccine Responsiveness after a Primary Meningococcal Vaccination in Middle-Aged Adults. Front Immunol 2018; 8:1962. [PMID: 29375578 PMCID: PMC5768620 DOI: 10.3389/fimmu.2017.01962] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Accepted: 12/19/2017] [Indexed: 01/08/2023] Open
Abstract
Introduction Prevention of infectious diseases in the elderly is essential to establish healthy aging. Yet, immunological aging impairs successful vaccination of the elderly. Predictive biomarkers for vaccine responsiveness in middle-aged adults may help to identify responders and non-responders before reaching old age. Therefore, we aimed to determine biomarkers associated with low and high responsiveness toward a primary vaccination in middle-aged adults, for which a tetravalent meningococcal vaccine was used as a model. Methods Middle-aged adults (50–65 years of age, N = 100), receiving a tetravalent meningococcal vaccination, were divided into low and high responders using the functional antibody titers at 28 days postvaccination. A total of 48 parameters, including absolute numbers of immune cells and serum levels of cytokines and biochemical markers, were determined prevaccination in all participants. Heat maps and multivariate redundancy analysis (RDA) were used to reveal immune phenotype characteristics and associations of the low and high responders. Results Several significant differences in prevaccination immune markers were observed between the low and high vaccine responders. Moreover, RDA analysis revealed a significant association between the prevaccination immune phenotype and vaccine responsiveness. In particular, our analysis pointed at high numbers of CD4 T cells, especially naïve CD4 and regulatory T subsets, to be associated with low vaccine responsiveness. In addition, low responders showed lower prevaccination IL-1Ra levels than high responders. Conclusion This explorative biomarker study shows associations between the prevaccination immune phenotype and vaccine responsiveness after a primary meningococcal vaccination in middle-aged adults. Consequently, these results provide a basis for predictive biomarker discovery for vaccine responsiveness that will require validation in larger cohort studies.
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Affiliation(s)
- Marieke van der Heiden
- Centre for Infectious Disease Control (Cib), National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands.,Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Centre Groningen, Groningen, Netherlands
| | - Guy A M Berbers
- Centre for Infectious Disease Control (Cib), National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands
| | - Susana Fuentes
- Centre for Infectious Disease Control (Cib), National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands
| | - Menno C van Zelm
- Department of Immunology, Erasmus MC, Rotterdam, Netherlands.,Department of Immunology and Pathology, Monash University and Alfred Hospital, Melbourne, VIC, Australia
| | - Annemieke M H Boots
- Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Centre Groningen, Groningen, Netherlands
| | - Anne-Marie Buisman
- Centre for Infectious Disease Control (Cib), National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands
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39
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Krishnan S, Vodovotz Y, Karg PE, Constantine G, Sowa GA, Constantine FJ, Brienza DM. Inflammatory Mediators Associated With Pressure Ulcer Development in Individuals With Pneumonia After Traumatic Spinal Cord Injury: A Pilot Study. Arch Phys Med Rehabil 2017; 98:1792-1799. [DOI: 10.1016/j.apmr.2016.12.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Revised: 12/21/2016] [Accepted: 12/23/2016] [Indexed: 10/20/2022]
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Zika virus preferentially replicates in the female reproductive tract after vaginal inoculation of rhesus macaques. PLoS Pathog 2017; 13:e1006537. [PMID: 28746373 PMCID: PMC5546709 DOI: 10.1371/journal.ppat.1006537] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Revised: 08/07/2017] [Accepted: 07/17/2017] [Indexed: 01/18/2023] Open
Abstract
Zika virus (ZIKV) is a mosquito-transmitted virus that can cause severe defects in an infected fetus. ZIKV is also transmitted by sexual contact, although the relative importance of sexual transmission is unclear. To better understand the role of sexual transmission in ZIKV pathogenesis, a nonhuman primate (NHP) model of vaginal transmission was developed. ZIKV was readily transmitted to mature cycling female rhesus macaque (RM) by vaginal inoculation with 104–106 plaque-forming units (PFU). However, there was variability in susceptibility between the individual RM with 1–>8 vaginal inoculations required to establish infection. After treatment with Depoprovera, a widely used contraceptive progestin, two RM that initially resisted 8 vaginal ZIKV inoculations became infected after one ZIKV inoculation. Thus, Depoprovera seemed to enhance susceptibility to vaginal ZIKV transmission. Unexpectedly, the kinetics of virus replication and dissemination after intravaginal ZIKV inoculation were markedly different from RM infected with ZIKV by subcutaneous (SQ) virus inoculation. Several groups have reported that after SQ ZIKV inoculation vRNA is rapidly detected in blood plasma with vRNA less common in urine and saliva and only rarely detected in female reproductive tract (FRT) secretions. In contrast, in vaginally inoculated RM, plasma vRNA is delayed for several days and ZIKV replication in, and vRNA shedding from, the FRT was found in all 6 animals. Further, after intravaginal transmission ZIKV RNA shedding from FRT secretions was detected before or simultaneously with plasma vRNA, and persisted for at least as long. Thus, ZIKV replication in the FRT was independent of, and often preceded virus replication in the tissues contributing to plasma vRNA. These results support the conclusion that ZIKV preferentially replicates in the FRT after vaginal transmission, but not after SQ transmission, and raise the possibility that there is enhanced fetal infection and pathology after vaginal ZIKV transmission compared to a mosquito transmitted ZIKV. Zika virus was introduced to Brazil in 2015 and it rapidly spread to all of tropical America. Although Zika virus infection is usually mild in adults, it can cause severe birth defects in the developing fetus that makes it critical to prevent ZIKV infection in women who are pregnant or who could become pregnant. Although Zika virus is transmitted primarily by mosquito bite, it can also be transmitted by sex. To understand the role of sexual transmission in Zika virus disease, we inoculated rhesus monkeys intravaginally with the virus and monitored virus in blood and reproductive tract secretions. ZIKV was detected in the female reproductive tract before it was detected in plasma and replication levels in the female reproductive tract did not reflect ZIKV levels in other parts of the body. Thus ZIKV prefers the reproductive tract after vaginal transmission suggesting that fetal disease could be more common or severe after vaginal ZIKV transmission compared to a mosquito transmitted ZIKV infection.
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Huttner A, Combescure C, Grillet S, Haks MC, Quinten E, Modoux C, Agnandji ST, Brosnahan J, Dayer JA, Harandi AM, Kaiser L, Medaglini D, Monath T, Roux-Lombard P, Kremsner PG, Ottenhoff THM, Siegrist CA. A dose-dependent plasma signature of the safety and immunogenicity of the rVSV-Ebola vaccine in Europe and Africa. Sci Transl Med 2017; 9:9/385/eaaj1701. [PMID: 28404856 DOI: 10.1126/scitranslmed.aaj1701] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Revised: 12/05/2016] [Accepted: 03/15/2017] [Indexed: 12/17/2022]
Abstract
The 2014-2015 Ebola epidemic affected several African countries, claiming more than 11,000 lives and leaving thousands with ongoing sequelae. Safe and effective vaccines could prevent or limit future outbreaks. The recombinant vesicular stomatitis virus-vectored Zaire Ebola (rVSV-ZEBOV) vaccine has shown marked immunogenicity and efficacy in humans but is reactogenic at higher doses. To understand its effects, we examined plasma samples from 115 healthy volunteers from Geneva who received low-dose (LD) or high-dose (HD) vaccine or placebo. Fifteen plasma chemokines/cytokines were assessed at baseline and on days 1, 2 to 3, and 7 after injection. Significant increases in monocyte-mediated MCP-1/CCL2, MIP-1β/CCL4, IL-6, TNF-α, IL-1Ra, and IL-10 occurred on day 1. A signature explaining 68% of cytokine/chemokine vaccine-response variability was identified. Its score was higher in HD versus LD vaccinees and was associated positively with vaccine viremia and negatively with cytopenia. It was higher in vaccinees with injection-site pain, fever, myalgia, chills, and headache; higher scores reflected increasing severity. In contrast, HD vaccinees who subsequently developed arthritis had lower day 1 scores than other HD vaccinees. Vaccine dose did not influence the signature despite its influence on specific outcomes. The Geneva-derived signature associated strongly (ρ = 0.97) with that of a cohort of 75 vaccinees from a parallel trial in Lambaréné, Gabon. Its score in Geneva HD vaccinees with subsequent arthritis was significantly lower than that in Lambaréné HD vaccinees, none of whom experienced arthritis. This signature, which reveals monocytes' critical role in rVSV-ZEBOV immunogenicity and safety across doses and continents, should prove useful in assessments of other vaccines.
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Affiliation(s)
- Angela Huttner
- Infection Control Program, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.,Division of Infectious Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.,Center for Vaccinology, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Christophe Combescure
- Division of Clinical Epidemiology, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Stéphane Grillet
- World Health Organization Collaborating Center for Vaccine Immunology, Faculty of Medicine, Geneva, Switzerland
| | - Mariëlle C Haks
- Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands
| | - Edwin Quinten
- Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands
| | - Christine Modoux
- Division of Immunology and Allergy, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Selidji Todagbe Agnandji
- Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon.,Institut für Tropenmedizin, Universitätsklinikum Tübingen, and German Center for Infection Research, Tübingen, Germany
| | | | - Julie-Anne Dayer
- Division of Infectious Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Ali M Harandi
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Laurent Kaiser
- Division of Infectious Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Donata Medaglini
- Laboratory of Molecular Microbiology and Biotechnology, Department of Medical Biotechnologies, University of Siena, Siena, Italy.,Sclavo Vaccines Association, Siena, Italy
| | - Tom Monath
- NewLink Genetics Corp., 94 Jackson Road, Devens, MA 01439, USA
| | | | - Pascale Roux-Lombard
- Division of Immunology and Allergy, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Peter G Kremsner
- Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon.,Institut für Tropenmedizin, Universitätsklinikum Tübingen, and German Center for Infection Research, Tübingen, Germany
| | - Tom H M Ottenhoff
- Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands
| | - Claire-Anne Siegrist
- Center for Vaccinology, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland. .,World Health Organization Collaborating Center for Vaccine Immunology, Faculty of Medicine, Geneva, Switzerland
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The relationship between pro-inflammatory cytokines and pain, appetite and fatigue in patients with advanced cancer. PLoS One 2017; 12:e0177620. [PMID: 28542626 PMCID: PMC5444654 DOI: 10.1371/journal.pone.0177620] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2016] [Accepted: 05/01/2017] [Indexed: 12/20/2022] Open
Abstract
Background Systemic inflammation is associated with reduced quality of life and increased symptoms in patients with advanced cancer. The aims of this study were to examine the relationships between inflammatory biomarkers and the Patient Reported Outcome Measures (PROMs) of pain, appetite and fatigue; and to explore whether levels of baseline biomarkers were associated with changes in these PROMs following treatment with corticosteroids. Material and methods An exploratory analysis was done on a trial examining the analgesic properties of corticosteroids in patients with advanced cancer. Inclusion criteria were: >18 years, taking opioids for moderate or severe cancer pain; pain ≥4 (numerical rating scale 0–10). Serum was extracted and levels of inflammatory biomarkers were assessed. PROMs of pain, appetite and fatigue were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30). The relationships between PROMs and inflammatory biomarkers were examined using Spearman Rho-Rank and multiple regression analysis. Results Data were available on 49 patients. Levels of sTNF-r1, IL-6, IL-18, MIF, MCP-1, TGF-β1, IL-1ra, and C-reactive protein (CRP) and Erythrocyte sedimentation rate (ESR) were elevated; IL-1β, IL-2, IL-4, IL-8, IL-10, IL-12(p70), interferon-γ, MIP-1α, and TNF-α were below the level of detection. The following correlations were observed: appetite and IL-6 and CRP; fatigue and IL-1ra (rs: 0.38–0.41, p< .01). There was no association between pretreatment biomarkers and effect from corticosteroid treatment. Conclusion In patients with advanced cancer and pain, some pro-inflammatory cytokines were related to appetite and fatigue. Inflammatory biomarkers were not associated with pain or with the efficacy of corticosteroid therapy. Further research examining the attenuation of the systemic inflammatory response and possible effects on symptoms would be of interest.
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Alcaraz-Quiles J, Titos E, Casulleras M, Pavesi M, López-Vicario C, Rius B, Lopategi A, de Gottardi A, Graziadei I, Gronbaek H, Ginès P, Bernardi M, Arroyo V, Clària J. Polymorphisms in the IL-1 gene cluster influence systemic inflammation in patients at risk for acute-on-chronic liver failure. Hepatology 2017; 65:202-216. [PMID: 27775822 DOI: 10.1002/hep.28896] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Accepted: 10/13/2016] [Indexed: 12/14/2022]
Abstract
UNLABELLED Acute-on-chronic liver failure (ACLF) in cirrhosis is an increasingly recognized syndrome characterized by acute decompensation, organ failure(s) and high short-term mortality. Recent findings suggest that an overexuberant systemic inflammation plays a primary role in ACLF progression. In this study, we examined whether genetic factors shape systemic immune responses in patients with decompensated cirrhosis. Six single-nucleotide polymorphisms (SNPs) in inflammation-related genes (interleukin [IL]-1 beta [IL-1β], rs1143623; IL-1 receptor antagonist [IL-1ra], rs4251961; IL-10, rs1800871; suppressor of cytokine signaling-3, rs4969170; nucleotide-binding oligomerization domain-containing protein 2, rs3135500; and chemerin chemokine-like receptor 1, rs1878022) were genotyped in 279 patients with cirrhosis with (n = 178) and without (n = 101) ACLF from the CANONIC study of the CLIF consortium. Among these SNPs, we identified two polymorphisms belonging to the IL-1 gene cluster (IL-1β and IL-1ra) in strong association with ACLF. Both SNPs were protective against ACLF; IL-1β (odds ratio [OR], 0.34, 95% confidence interval [CI], 0.13-0.89; P < 0.05) and IL-1ra (OR, 0.58; 95% CI, 0.35-0.95; P < 0.05) under the recessive and overdominant inheritance models, respectively. These protective SNPs translated into reduced circulating levels of IL-1β, IL-1α, IL-6, granulocyte-colony stimulating factor, granulocyte-macrophage colony-stimulating factor, and C-reactive protein at enrollment as well as after 7-14 days of admission. These findings were confirmed in vitro in leukocytes incubated with plasma from patients with decompensated cirrhosis carrying the protective SNP genotypes. Notably, a higher frequency of the protective genotypes was observed in patients without (80%) than in those with (20%) ACLF. Consistently, patients carrying the combined protective genotypes showed a lower 28-day mortality rate. CONCLUSION These data identify two common functional polymorphisms in the IL-1 gene cluster, which are associated with the inflammatory process related to development of ACLF. (Hepatology 2017;65:202-216).
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Affiliation(s)
- José Alcaraz-Quiles
- Department of Biochemistry and Molecular Genetics (CDB), Hospital Clínic, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Esther Titos
- Department of Biochemistry and Molecular Genetics (CDB), Hospital Clínic, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.,Biomedical Research Networking Center on Liver and Digestive Diseases (CIBERehd)
| | - Mireia Casulleras
- Department of Biochemistry and Molecular Genetics (CDB), Hospital Clínic, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Marco Pavesi
- European Foundation for the Study of Chronic Liver Failure (EF-CLIF) and EASL-CLIF Consortium
| | - Cristina López-Vicario
- Department of Biochemistry and Molecular Genetics (CDB), Hospital Clínic, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Bibiana Rius
- Department of Biochemistry and Molecular Genetics (CDB), Hospital Clínic, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Aritz Lopategi
- Department of Biochemistry and Molecular Genetics (CDB), Hospital Clínic, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | | | | | | | - Pere Ginès
- Biomedical Research Networking Center on Liver and Digestive Diseases (CIBERehd).,Liver Unit, Hospital Clínic, Barcelona, Spain
| | - Mauro Bernardi
- European Foundation for the Study of Chronic Liver Failure (EF-CLIF) and EASL-CLIF Consortium
| | - Vicente Arroyo
- European Foundation for the Study of Chronic Liver Failure (EF-CLIF) and EASL-CLIF Consortium
| | - Joan Clària
- Department of Biochemistry and Molecular Genetics (CDB), Hospital Clínic, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.,Biomedical Research Networking Center on Liver and Digestive Diseases (CIBERehd).,Department of Biomedical Sciences, University of Barcelona, Barcelona, Spain
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Abstract
Convergent evidence indicates that abnormalities in the innate immune system may be pertinent to the pathogenesis, phenomenology, and possible treatment of several mental disorders. In keeping with this view, the targeting of interleukin-6 with the human monoclonal antibody sirukumab may represent a possible treatment and disease modification approach, for adults with brain-based disorders (e.g., major depressive disorder). A PubMed/Medline database search was performed using the following search terms: sirukumab; anti-IL-6; IL-6; major depressive disorder; inflammation. A systematic review was conducted of both preclinical and clinical trials reporting on the pharmacology of sirukumab or investigating the efficacy of targeting IL-6 signaling. Overall, sirukumab has been reported to be a safe and well-tolerated agent, capable of modulating the immune response in healthy populations as well as in subjects with inflammatory disorders (e.g., rheumatoid arthritis). Sirukumab's effects on cytokine networks as part of the innate immune system provide a coherent rationale for possible application in neuropsychiatric disorders with possible benefits across several domains of the biobehavioral Research Domain Criteria matrix (e.g., general cognitive processes, positive valence systems). Amongst individuals with complex brain-based disorders (e.g., mood disorders), the dimensions/domains most likely to benefit with sirukumab are negative valence disturbances (e.g., anxiety, depression, rumination), positive valence disturbances (e.g., anhedonia) as well as general cognitive processes. We suggest that sirukumab represents a prototype and possibly a proof-of-concept that agents that engage IL-6 targets have salutary effects in psychiatry.
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Sadowsky D, Zamora R, Barclay D, Yin J, Fontes P, Vodovotz Y. Machine Perfusion of Porcine Livers with Oxygen-Carrying Solution Results in Reprogramming of Dynamic Inflammation Networks. Front Pharmacol 2016; 7:413. [PMID: 27867357 PMCID: PMC5095594 DOI: 10.3389/fphar.2016.00413] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2016] [Accepted: 10/18/2016] [Indexed: 01/28/2023] Open
Abstract
Background:Ex vivo machine perfusion (MP) can better preserve organs for transplantation. We have recently reported on the first application of an MP protocol in which liver allografts were fully oxygenated, under dual pressures and subnormothermic conditions, with a new hemoglobin-based oxygen carrier (HBOC) solution specifically developed for ex vivo utilization. In those studies, MP improved organ function post-operatively and reduced inflammation in porcine livers. Herein, we sought to refine our knowledge regarding the impact of MP by defining dynamic networks of inflammation in both tissue and perfusate. Methods: Porcine liver allografts were preserved either with MP (n = 6) or with cold static preservation (CSP; n = 6), then transplanted orthotopically after 9 h of preservation. Fourteen inflammatory mediators were measured in both tissue and perfusate during liver preservation at multiple time points, and analyzed using Dynamic Bayesian Network (DyBN) inference to define feedback interactions, as well as Dynamic Network Analysis (DyNA) to define the time-dependent development of inflammation networks. Results: Network analyses of tissue and perfusate suggested an NLRP3 inflammasome-regulated response in both treatment groups, driven by the pro-inflammatory cytokine interleukin (IL)-18 and the anti-inflammatory mediator IL-1 receptor antagonist (IL-1RA). Both DyBN and DyNA suggested a reduced role of IL-18 and increased role of IL-1RA with MP, along with increased liver damage with CSP. DyNA also suggested divergent progression of responses over the 9 h preservation time, with CSP leading to a stable pattern of IL-18-induced liver damage and MP leading to a resolution of the pro-inflammatory response. These results were consistent with prior clinical, biochemical, and histological findings after liver transplantation. Conclusion: Our results suggest that analysis of dynamic inflammation networks in the setting of liver preservation may identify novel diagnostic and therapeutic modalities.
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Affiliation(s)
- David Sadowsky
- Department of Surgery, University of Pittsburgh, Pittsburgh PA, USA
| | - Ruben Zamora
- Department of Surgery, University of Pittsburgh, PittsburghPA, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, PittsburghPA, USA
| | - Derek Barclay
- Department of Surgery, University of Pittsburgh, Pittsburgh PA, USA
| | - Jinling Yin
- Department of Surgery, University of Pittsburgh, Pittsburgh PA, USA
| | - Paulo Fontes
- Department of Surgery, University of Pittsburgh, PittsburghPA, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, PittsburghPA, USA; Department of Surgery, Thomas E. Starzl Transplantation Institute, PittsburghPA, USA
| | - Yoram Vodovotz
- Department of Surgery, University of Pittsburgh, PittsburghPA, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, PittsburghPA, USA
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Cytokine production by PBMC and serum from allergic and non-allergic subjects following in vitro histamine stimulation to test fexofenadine and osthole anti-allergic properties. Eur J Pharmacol 2016; 791:763-772. [PMID: 27756601 DOI: 10.1016/j.ejphar.2016.10.020] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Revised: 10/14/2016] [Accepted: 10/14/2016] [Indexed: 11/21/2022]
Abstract
FXF is a third-generation antihistamine drug and osthole is assumed a natural antihistamine alternative. This paper compares peripheral blood mononuclear cell (PBMC) incubation with FXF and osthole, by studying FXF, osthole and histamine cytokine secretion in PBMC in vitro cultures. Mabtech kits determined the interleukins IL-1β, IL-4, IL-10, IL-13 and TNF-α. The influence of the above active substances on cytokine secretion in PBMC's and serum was assessed: cytokines were IL-1β, IL-4, IL-10, IL-13 and TNF-α; and cytokine levels secreted by untreated PBMCs in pure culture medium formed the absolute control (ctrl). We determined that osthole affects PBMC cytokine secretion to almost precisely the same extent as FXF (IL-1β, IL-4, IL-10 and TNF). In addition osthole had greater IL-13 blocking ability than FXF. Moreover, we observed significantly decreased IL-4 level in histamine/osthole theatment compared to histamine alone. Meanwhile, FXF not significantly decrease the level of IL-4 increased by histamine. This data indicates osthole's strong role in allergic inflamation. All results confirm our hypothesis that osthole is a natural histamine antagonist and therefore can be beneficially used in antihistamine treatment of conditions such as allergies.
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Pedersen BK. State of the Art Reviews: Health Benefits Related to Exercise in Patients With Chronic Low-Grade Systemic Inflammation. Am J Lifestyle Med 2016. [DOI: 10.1177/1559827607301410.] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Today, there is substantial evidence to suggest that regular exercise has health-promoting effects, which are beyond its effect on weight control. Regular exercise offers protection against all-cause mortality, and there is evidence from randomized intervention studies that physical training is effective as a treatment in patients with chronic heart diseases, type 2 diabetes, and symptoms related with the metabolic syndrome. Chronic diseases such as cardiovascular disease and type 2 diabetes are associated with chronic low-grade systemic inflammation. This review focuses on the anti-inflammatory effects of exercise that are mediated by muscle-derived cytokines (myokines). It is suggested that myokines may be involved in mediating the health-beneficial effects of exercise and that these in particular are involved in the protection against chronic diseases associated with low-grade inflammation.
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Cavaillon JM, Annane D. Invited review: Compartmentalization of the inflammatory response in sepsis and SIRS. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/09680519060120030301] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Sepsis and systemic inflammatory response syndrome (SIRS) are associated with an exacerbated production of both pro- and anti-inflammatory mediators that are mainly produced within tissues. Although a systemic process, the pathophysiological events differ from organ to organ, and from organ to peripheral blood, leading to the concept of compartmentalization. The nature of the insult ( e.g. burn, hemorrhage, trauma, peritonitis), the cellular composition of each compartment ( e.g . nature of phagocytes, nature of endothelial cells), and its micro-environment ( e.g. local presence of granulocyte-macrophage colony stimulating factor [GM-CSF] in the lungs, low levels of arginine in the liver, release of endotoxin from the gut), and leukocyte recruitment, have a great influence on local inflammation and on tissue injury. High levels of pro-inflammatory mediators ( e.g. interleukin-1 [IL-1], tumor necrosis factor [TNF], gamma interferon [IFN-γ], high mobility group protein-1 [HMGB1], macrophage migration inhibitory factor [MIF]) produced locally and released into the blood stream initiate remote organ injury as a consequence of an organ cross-talk. The inflammatory response within the tissues is greatly influenced by the local delivery of neuromediators by the cholinergic and sympathetic neurons. Acetylcholine and epinephrine contribute with IL-10 and other mediators to the anti-inflammatory compensatory response initiated to dampen the inflammatory process. Unfortunately, this regulatory response leads to an altered immune status of leukocytes that can increase the susceptibility to further infection. Again, the nature of the insult, the nature of the leukocytes, the presence of circulating microbial components, and the nature of the triggering agent employed to trigger cells, greatly influence the immune status of the leukocytes that may differ from one compartment to another. While anti-inflammatory mediators predominate within the blood stream to avoid igniting new inflammatory foci, their presence within tissues may not always be sufficient to prevent the initiation of a deleterious inflammatory response in the different compartments.
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Affiliation(s)
| | - Djillali Annane
- Service de Réanimation, Hôpital Raymond Poincaré, Assistance Publique - Hôpitaux de Paris, Faculté de Médecine Paris Ile de France Ouest, Université de Versailles Saint-Quentin-en-Yvelines, Garches, France
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Tilg H, Moschen AR, Szabo G. Interleukin-1 and inflammasomes in alcoholic liver disease/acute alcoholic hepatitis and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology 2016; 64:955-65. [PMID: 26773297 DOI: 10.1002/hep.28456] [Citation(s) in RCA: 244] [Impact Index Per Article: 27.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Accepted: 01/09/2016] [Indexed: 12/12/2022]
Abstract
UNLABELLED Both alcoholic liver disease (ALD) and nonalcoholic fatty liver disease are characterized by massive lipid accumulation in the liver accompanied by inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma in a substantial subgroup of patients. At several stages in these diseases, mediators of the immune system, such as cytokines or inflammasomes, are crucially involved. In ALD, chronic ethanol exposure sensitizes Kupffer cells to activation by lipopolysaccharides through Toll-like receptors, e.g., Toll-like receptor 4. This sensitization enhances the production of various proinflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-alpha, thereby contributing to hepatocyte dysfunction, necrosis, and apoptosis and the generation of extracellular matrix proteins leading to fibrosis/cirrhosis. Indeed, neutralization of IL-1 by IL-1 receptor antagonist has recently been shown to potently prevent liver injury in murine models of ALD. As IL-1 is clearly linked to key clinical symptoms of acute alcoholic hepatitis such as fever, neutrophilia, and wasting, interfering with the IL-1 pathway might be an attractive treatment strategy in the future. An important role for IL-1-type cytokines and certain inflammasomes has also been demonstrated in murine models of nonalcoholic fatty liver disease. IL-1-type cytokines can regulate hepatic steatosis; the NLR family pyrin domain containing 3 inflammasome is critically involved in metabolic dysregulation. CONCLUSION IL-1 cytokine family members and various inflammasomes mediate different aspects of both ALD and nonalcoholic fatty liver disease. (Hepatology 2016;64:955-965).
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Affiliation(s)
- Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Alexander R Moschen
- Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Gyongyi Szabo
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USAMA
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Montazeri M, Sanchez-Lopez JA, Caballero I, Maslehat Lay N, Elliott S, Fazeli A. Interleukin-1 receptor antagonist mediates toll-like receptor 3-induced inhibition of trophoblast adhesion to endometrial cells in vitro. Hum Reprod 2016; 31:2098-107. [PMID: 27412245 DOI: 10.1093/humrep/dew171] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Accepted: 06/13/2016] [Indexed: 01/10/2023] Open
Abstract
STUDY QUESTION Is interleukin-1 receptor antagonist (IL-1RA) involved in the toll-like receptor 3 (TLR 3)-induced inhibition of trophoblast cells' adhesion to endometrial cells in vitro? SUMMARY ANSWER IL-1RA mediates the TLR 3-induced inhibition of trophoblast cells' adhesion to endometrial cells in vitro. WHAT IS KNOWN ALREADY It is well documented that endometrial TLR 3 activation leads to impairment of trophoblast binding to endometrial cells in vitro. IL-1RA is known as an anti-implantation factor, as its injection significantly reduced implantation rates in mice by an effect on endometrial receptivity. STUDY DESIGN, SIZE, DURATION Poly I:C was used as a TLR3 specific ligand and endometrial cells were either treated or not with Poly I:C (treated versus control) in vitro. IL-1RA was applied to block IL-1 signal transduction. IL-1RA was knocked down by Accell Human IL1RN siRNA. Flagellin was used to stimulate TLR 5. SP600125 (JNK) was applied to inhibit the mitogen-activated protein kinases (MAPK) pathway. BAY11 -7082 was used to inhibit the nuclear factor-κB (NF-κB) pathway. The experiments were performed in three replicates on three separate days. PARTICIPANTS/MATERIALS, SETTING, METHODS An in vitro assay was developed using RL95-2 (an endometrial cell line) and JAr (a trophoblast cell line) cells. Initially, the production of IL-1RA in RL95-2 cells in response to TLR 3 activation was measured. To determine whether the TLR 3-induced inhibition of trophoblast binding was mediated through IL-1RA: (i) we evaluated the effect of IL-1RA on the attachment of trophoblast cells to endometrial cells; (ii) we knocked down TLR3-induced IL-1RA gene expression by IL-1RA Small interfering RNA (siRNA) and evaluated trophoblast attachment to endometrial cells. Finally, to clarify through which pathway TLR 3-induced inhibition of trophoblast binding occurs: (i) activation of NF-κB and MAPK was detected by transfecting the cells with secreted placental alkaline phosphatase reporter plasmids bearing promoter sequences for each transcription factor; (ii) the inhibitors for NF-κB and MAPK were used to block signaling; (iii) it was then investigated whether addition of these inhibitors could restore the TLR 3-induced impairment of trophoblast attachment to the endometrial cells. MAIN RESULTS AND THE ROLE OF CHANCE Our results showed that addition of polyinosinic:polycytidylic acid (Poly I:C) to RL95-2 cells significantly increased the production of IL-1RA (P < 0.05). Addition of human recombinant IL-1RA to RL95-2 cells remarkably decreased the adhesion rate of trophoblast cells to endometrial cells (P < 0.05). In addition, suppression of TLR3-induced IL-1RA gene expression in RL95-2 cells significantly restored trophoblast cells attachment to endometrial cells in the presence of Poly I:C (P < 0.05). Only TLR3 and not TLR5 induced MAPK activation (P < 0.05). TLR3 ligation did not affect NF-κB activation. Of NF-kB and MAPK inhibitors, only MAPK's inhibitor could achieve restoration of spheroid adhesion to endometrial cells (P < 0.05). LIMITATIONS, REASONS FOR CAUTION This study has been only done in vitro. Future in vivo studies will confirm our data. WIDER IMPLICATIONS OF THE FINDINGS The findings of this study have a potential clinical application in introducing IL-1RA as one of the diagnostic infertility markers in the endometrium, which can affect the process of embryo adhesion at the time of implantation. Moreover, based on the novel data obtained in the current study, blocking and regulating the MAPK pathway by its inhibitors can be used as a new strategy to prevent and treat virus-induced infertility cases in ART techniques. STUDY FUNDING/COMPETING INTEREST This study was partially funded by a Marie Curie IIF-253948 grant to I.C. and was partially funded by the author's institutions. The authors have no conflict of interest to declare.
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Affiliation(s)
- M Montazeri
- Academic Unit of Reproductive and Developmental Medicine, The University of Sheffield, Level 4, Jessop Wing, Tree Root Walk, Sheffield S10 2SF, UK
| | - J A Sanchez-Lopez
- Academic Unit of Reproductive and Developmental Medicine, The University of Sheffield, Level 4, Jessop Wing, Tree Root Walk, Sheffield S10 2SF, UK
| | - I Caballero
- Academic Unit of Reproductive and Developmental Medicine, The University of Sheffield, Level 4, Jessop Wing, Tree Root Walk, Sheffield S10 2SF, UK UMR1282 ISP, INRA, Nouzilly, France
| | - N Maslehat Lay
- Academic Unit of Reproductive and Developmental Medicine, The University of Sheffield, Level 4, Jessop Wing, Tree Root Walk, Sheffield S10 2SF, UK
| | - S Elliott
- Academic Unit of Reproductive and Developmental Medicine, The University of Sheffield, Level 4, Jessop Wing, Tree Root Walk, Sheffield S10 2SF, UK
| | - A Fazeli
- Academic Unit of Reproductive and Developmental Medicine, The University of Sheffield, Level 4, Jessop Wing, Tree Root Walk, Sheffield S10 2SF, UK
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