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Lee KMC, Lupancu T, Chang L, Manthey CL, Zeeman M, Fourie AM, Hamilton JA. The mode of action of IL-23 in experimental inflammatory arthritic pain and disease. Arthritis Res Ther 2024; 26:148. [PMID: 39107827 PMCID: PMC11302168 DOI: 10.1186/s13075-024-03380-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 07/22/2024] [Indexed: 08/10/2024] Open
Abstract
OBJECTIVES We have previously reported using gene-deficient mice that the interleukin (IL)-23p19 subunit is required for the development of innate immune-driven arthritic pain and disease. We aimed to explore here, using a number of in vivo approaches, how the IL-23p19 subunit can mechanistically control arthritic pain and disease in a T- and B- lymphocyte-independent manner. METHODS We used the zymosan-induced arthritis (ZIA) model in wild-type and Il23p19-/- mice, by a radiation chimera approach, and by single cell RNAseq and qPCR analyses, to identify the IL23p19-expressing and IL-23-responding cell type(s) in the inflamed joints. This model was also utilized to investigate the efficacy of IL-23p19 subunit blockade with a neutralizing monoclonal antibody (mAb). A novel IL-23-driven arthritis model was established, allowing the identification of putative downstream mediators of IL-23 in the control of pain and disease. Pain and arthritis were assessed by relative static weight distribution and histology, respectively. RESULTS We present evidence that (i) IL-23p19+ non-bone marrow-derived macrophages are required for the development of ZIA pain and disease, (ii) prophylactic and therapeutic blockade of the IL-23p19 subunit ameliorate ZIA pain and disease and (iii) systemically administered IL-23 can induce arthritic pain and disease in a manner dependent on TNF, GM-CSF, CCL17 and cyclooxygenase activity, but independently of lymphocytes, CGRP, NGF and substance P. CONCLUSIONS The data presented should aid IL-23 targeting both in the choice of inflammatory disease to be treated and the design of clinical trials.
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Affiliation(s)
- Kevin M-C Lee
- Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, 3050, Australia.
| | - Tanya Lupancu
- Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, 3050, Australia
| | - Leon Chang
- Janssen Research & Development, San Diego, CA, USA
| | | | - Martha Zeeman
- Janssen Research & Development, Spring House, PA, USA
| | | | - John A Hamilton
- Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, 3050, Australia
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2
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Orchard T, McLaughlin E, Winschel T, Shadyab A, Laddu D, Vitolins M, Constantinescu F, Jackson R. Fatty Acid Intake and Polyunsaturated Fatty Acid Biomarkers and Risk of Total Knee or Hip Arthroplasty Among Older Women in the Women's Health Initiative. Arthritis Care Res (Hoboken) 2024; 76:993-1005. [PMID: 38412867 PMCID: PMC11209811 DOI: 10.1002/acr.25319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 01/23/2024] [Accepted: 02/23/2024] [Indexed: 02/29/2024]
Abstract
OBJECTIVE The objective was to determine whether baseline fatty acid intake and erythrocyte omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) can predict risk of total hip arthroplasty (THA) and total knee arthroplasty (TKA) in older women. METHODS This was a prospective analysis of 34,990 women in the Women's Health Initiative. Dietary fatty acids were estimated from food frequency questionnaires. Imputed erythrocyte PUFAs were available in a subcohort of 3,428 women. Arthroplasty (THA and TKA), used as a surrogate of severe osteoarthritis, was identified via linked Medicare data. Cox proportional hazards models were constructed to estimate risk of arthroplasty. RESULTS Risk of THA was associated with higher intake of arachidonic acid, (multivariable hazard ratio [HR] quartile 4 [Q4] vs Q1: 1.16; 95% confidence interval [CI] 1.01-1.34; P = 0.03) and higher intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA; HR Q4 vs Q1: 1.20; 95% CI 1.05-1.39; P = 0.003). There was a linear trend (P = 0.04) for patients to have a higher risk of THA with higher erythrocyte EPA and DHA in body mass index-adjusted models; however, there was no significant difference in patients who had THAs by quartiles of erythrocyte EPA and DHA (P = 0.10). Dietary fatty acids and erythrocyte PUFAs were not significantly associated with risk of TKA. CONCLUSION Higher baseline intakes of arachidonic acid and EPA and DHA were associated with a modestly higher risk of THA. No association was found between fatty acids and patients who had TKAs. Further research in populations with direct measures of osteoarthritis severity is needed to better understand the importance of PUFAs in modulating osteoarthritis and arthroplasty risk.
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MESH Headings
- Humans
- Female
- Arthroplasty, Replacement, Hip/adverse effects
- Arthroplasty, Replacement, Knee
- Aged
- Prospective Studies
- Biomarkers/blood
- Women's Health
- Osteoarthritis, Hip/surgery
- Osteoarthritis, Hip/blood
- Osteoarthritis, Knee/surgery
- Osteoarthritis, Knee/blood
- Risk Factors
- Erythrocytes/chemistry
- Erythrocytes/metabolism
- Fatty Acids, Omega-6/blood
- Fatty Acids, Unsaturated/blood
- United States/epidemiology
- Fatty Acids, Omega-3/blood
- Fatty Acids, Omega-3/administration & dosage
- Risk Assessment
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Affiliation(s)
| | | | | | | | - Deepika Laddu
- Arbor Research Collaborative for Health, Ann Arbor, MI
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Xie ZX, Li Y, Yang AM, Wu D, Wang Q. Pathogenesis of chronic enteropathy associated with the SLCO2A1 gene: Hypotheses and conundrums. World J Gastroenterol 2024; 30:2505-2511. [PMID: 38817656 PMCID: PMC11135407 DOI: 10.3748/wjg.v30.i19.2505] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 03/18/2024] [Accepted: 04/25/2024] [Indexed: 05/20/2024] Open
Abstract
Chronic enteropathy associated with the SLCO2A1 gene (CEAS) is a complex gastroenterological condition characterized by multiple ulcers in the small intestine with chronic bleeding and protein loss. This review explores the potential mechanisms underlying the pathogenesis of CEAS, focusing on the role of SLCO2A1-encoded prostaglandin transporter OATP2A1 and its impact on prostaglandin E2 (PGE2) levels. Studies have suggested that elevated PGE2 levels contribute to mucosal damage, inflammation, and disruption of the intestinal barrier. The effects of PGE2 on macrophage activation and Maxi-Cl channel functionality, as well as its interaction with nonsteroidal anti-inflammatory drugs play crucial roles in the progression of CEAS. Understanding the balance between its protective and pro-inflammatory effects and the complex interactions within the gastrointestinal tract can shed light on potential therapeutic targets for CEAS and guide the development of novel, targeted therapies.
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Affiliation(s)
- Zhi-Xin Xie
- State Key Laboratory of Complex Severe and Rare Diseases, Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
- Department of Clinical Medicine, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Yue Li
- State Key Laboratory of Complex Severe and Rare Diseases, Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Ai-Ming Yang
- State Key Laboratory of Complex Severe and Rare Diseases, Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Dong Wu
- State Key Laboratory of Complex Severe and Rare Diseases, Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Qiang Wang
- State Key Laboratory of Complex Severe and Rare Diseases, Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
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4
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Kanno T, Nakajima T, Miyako K, Endo Y. Lipid metabolism in Th17 cell function. Pharmacol Ther 2023; 245:108411. [PMID: 37037407 DOI: 10.1016/j.pharmthera.2023.108411] [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: 01/29/2023] [Revised: 03/31/2023] [Accepted: 04/04/2023] [Indexed: 04/12/2023]
Abstract
Among the subset of T helper cells, Th17 cells are known to play a crucial role in the pathogenesis of various autoimmune disorders, such as psoriasis, rheumatoid arthritis, inflammatory bowel disease, steroid-resistant asthma, and multiple sclerosis. The master transcription factor retinoid-related orphan receptor gamma t (RORγt), a nuclear hormone receptor, plays a vital role in inducing Th17-cell differentiation. Recent findings suggest that metabolic control is critical for Th17-cell differentiation, particularly through the engagement of de novo lipid biosynthesis. Inhibition of lipid biosynthesis, either through the use of pharmacological inhibitors or by the deficiency of related enzymes in CD4+ T cells, results in significant suppression of Th17-cell differentiation. Mechanistic studies indicate that metabolic fluxes through both the fatty acid and cholesterol biosynthetic pathways are essential for controlling RORγt activity through the generation of a lipid ligand of RORγt. This review highlights recent findings that underscore the significant role of lipid metabolism in the differentiation and function of Th17 cells, as well as elucidating the distinctive molecular pathways that drive the activation of RORγt by cellular lipid metabolism. We further elaborate on a pioneering therapeutic approach for ameliorating autoimmune disorders via the inhibition of RORγt.
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Affiliation(s)
- Toshio Kanno
- Department of Frontier Research and Development, Laboratory of Medical Omics Research, Kazusa DNA Research Institute, 2-6-7 Kazusa Kamatari, Kisarazu, Chiba 292-0818, Japan
| | - Takahiro Nakajima
- Department of Frontier Research and Development, Laboratory of Medical Omics Research, Kazusa DNA Research Institute, 2-6-7 Kazusa Kamatari, Kisarazu, Chiba 292-0818, Japan
| | - Keisuke Miyako
- Department of Frontier Research and Development, Laboratory of Medical Omics Research, Kazusa DNA Research Institute, 2-6-7 Kazusa Kamatari, Kisarazu, Chiba 292-0818, Japan
| | - Yusuke Endo
- Department of Frontier Research and Development, Laboratory of Medical Omics Research, Kazusa DNA Research Institute, 2-6-7 Kazusa Kamatari, Kisarazu, Chiba 292-0818, Japan.
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Zhang LB, Yan Y, He J, Wang PP, Chen X, Lan TY, Guo YX, Wang JP, Luo J, Yan ZR, Xu Y, Tao QW. Epimedii Herba: An ancient Chinese herbal medicine in the prevention and treatment of rheumatoid arthritis. Front Chem 2022; 10:1023779. [PMID: 36465876 PMCID: PMC9712800 DOI: 10.3389/fchem.2022.1023779] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Accepted: 11/02/2022] [Indexed: 08/29/2023] Open
Abstract
Rheumatoid arthritis (RA) is a chronic, progressive inflammatory and systemic autoimmune disease resulting in severe joint destruction, lifelong suffering and considerable disability. Diverse prescriptions of traditional Chinese medicine (TCM) containing Epimedii Herba (EH) achieve greatly curative effects against RA. The present review aims to systemically summarize the therapeutic effect, pharmacological mechanism, bioavailability and safety assessment of EH to provide a novel insight for subsequent studies. The search terms included were "Epimedii Herba", "yinyanghuo", "arthritis, rheumatoid" and "Rheumatoid Arthritis", and relevant literatures were collected on the database such as Google Scholar, Pubmed, Web of Science and CNKI. In this review, 15 compounds from EH for the treatment of RA were summarized from the aspects of anti-inflammatory, immunoregulatory, cartilage and bone protective, antiangiogenic and antioxidant activities. Although EH has been frequently used to treat RA in clinical practice, studies on mechanisms of these activities are still scarce. Various compounds of EH have the multifunctional traits in the treatment of RA, so EH may be a great complementary medicine option and it is necessary to pay more attention to further research and development.
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Affiliation(s)
- Liu-Bo Zhang
- Department of TCM Rheumatism, Department of Pharmacy, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
- China-Japan Friendship Clinical Medical College & School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Yu Yan
- Department of TCM Rheumatism, Department of Pharmacy, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Jun He
- Department of TCM Rheumatism, Department of Pharmacy, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Pei-Pei Wang
- China-Japan Friendship Clinical Medical College & School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Xin Chen
- School of Chinese Medicine, Shenyang Pharmaceutical University, Shenyang, China
| | - Tian-Yi Lan
- Department of TCM Rheumatism, Department of Pharmacy, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
- China-Japan Friendship Clinical Medical College & School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Yu-Xuan Guo
- Department of TCM Rheumatism, Department of Pharmacy, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
- China-Japan Friendship Clinical Medical College & School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Jin-Ping Wang
- Department of TCM Rheumatism, Department of Pharmacy, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Jing Luo
- Department of TCM Rheumatism, Department of Pharmacy, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Ze-Ran Yan
- Department of TCM Rheumatism, Department of Pharmacy, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Yuan Xu
- Department of TCM Rheumatism, Department of Pharmacy, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Qing-Wen Tao
- Department of TCM Rheumatism, Department of Pharmacy, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
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Allergic airway inflammation induces upregulation of the expression of IL-23R by macrophages and not in CD3 + T cells and CD11c +F4/80 - dendritic cells of the lung. Cell Tissue Res 2022; 389:85-98. [PMID: 35475923 PMCID: PMC9200692 DOI: 10.1007/s00441-021-03538-0] [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: 02/24/2021] [Accepted: 10/06/2021] [Indexed: 11/05/2022]
Abstract
Interleukin 23 and the interleukin 23 receptor (IL-23-IL23R) are described as the major enhancing factors for Interleukin 17 (IL-17) in allergic airway inflammation. IL-17 is considered to induce neutrophilic inflammation in the lung, which is often observed in severe, steroid-resistant asthma-phenotypes. For that reason, understanding of IL-23 and IL-17 axis is very important for future therapy strategies, targeting neutrophil pathway of bronchial asthma. This study aimed to investigate the distribution and expression of IL-23R under physiological and inflammatory conditions. Therefore, a house dust mite (HDM) model of allergic airway inflammation was performed by treating mice with HDM intranasally. Immunofluorescence staining with panel of antibodies was performed in lung tissues to examine the macrophage, dendritic cell, and T cell subpopulations. The allergic airway inflammation was quantified by histopathological analysis, ELISA measurements, and airway function. HDM-treated mice exhibited a significant allergic airway inflammation including higher amounts of NE+ cells in lung parenchyma. We found only a small amount of IL-23R positives, out of total CD3+T cells, and no upregulation in HDM-treated animals. In contrast, the populations of F4/80+ macrophages and CD11c+F4/80− dendritic cells (DCs) with IL-23R expression were found to be higher. But HDM treatment leads to a significant increase of IL-23R+ macrophages, only. IL-23R was expressed by every examined macrophage subpopulation, whereas only Mϕ1 and hybrids between Mϕ1 and Mϕ2 phenotype and not Mϕ2 were found to upregulate IL-23R. Co-localization of IL-23R and IL-17 was only observed in F4/80+ macrophages, suggesting F4/80+ macrophages express IL-23R along with IL-17 in lung tissue. The study revealed that macrophages involving the IL-23 and IL-17 pathway may provide a potential interesting therapeutic target in neutrophilic bronchial asthma.
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Lee KMC, Sherlock JP, Hamilton JA. The role of interleukin (IL)-23 in regulating pain in arthritis. Arthritis Res Ther 2022; 24:89. [PMID: 35468842 PMCID: PMC9036686 DOI: 10.1186/s13075-022-02777-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 01/12/2022] [Indexed: 11/10/2022] Open
Abstract
Current understanding of IL-23 biology, with its link to other pro-inflammatory cytokines, for example, IL-17 and granulocyte macrophage-colony stimulating factor (GM-CSF), is primarily focused on T lymphocyte-mediated inflammation/autoimmunity. Pain is a significant symptom associated with many musculoskeletal conditions leading to functional impairment and poor quality of life. While the role of IL-23 in arthritis has been studied in mouse models of adaptive immune-mediated arthritis using targeted approaches (e.g., monoclonal antibody (mAb) neutralization), the literature on IL-23 and arthritis pain is limited. Encouragingly, the anti-IL-23p19 mAb, guselkumab, reduces pain in psoriatic arthritis patients. Recent evidence has suggested a new biology for IL-23, whereby IL-23 is required in models of innate immune-mediated arthritis and its associated pain with its action being linked to a GM-CSF-dependent pathway (the so-called GM-CSF➔CCL17 pathway). This Commentary discusses the current understanding of potential cytokine networks involving IL-23 in arthritis pain and provides a rationale for future clinical studies targeting IL-23p19 in arthritis pain.
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Affiliation(s)
- Kevin M-C Lee
- The University of Melbourne, Department of Medicine, Royal Melbourne Hospital, Parkville, Victoria, Australia.
| | - Jonathan P Sherlock
- Janssen Research and Development LLC, Spring House, PA, USA.,Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - John A Hamilton
- The University of Melbourne, Department of Medicine, Royal Melbourne Hospital, Parkville, Victoria, Australia.,Australian Institute for Musculoskeletal Science (AIMSS), The University of Melbourne and Western Health, St. Albans, Victoria, Australia
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Coras R, Kavanaugh A, Kluzniak A, Holt D, Weilgosz A, Aaron A, Quehenberger O, Ritchlin C, Guma M. Differences in oxylipin profile in psoriasis versus psoriatic arthritis. Arthritis Res Ther 2021; 23:200. [PMID: 34303373 PMCID: PMC8310583 DOI: 10.1186/s13075-021-02575-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 07/06/2021] [Indexed: 01/02/2023] Open
Abstract
Background Oxylipins are biological lipids that have been implicated in inflammation. We previously found that certain oxylipins correlated with clinical manifestations in psoriatic arthritis (PsA) patients. Here, we compare oxylipin profiles in PsA patients and those with psoriasis (PsO) without inflammatory arthritis to identify oxylipins that associate with specific disease manifestations to better understand disease pathogenesis and identify new biomarkers. Methods Consecutive patients with PsA (who met the CASPAR classification criteria for PsA) and PsO were recruited from the Rheumatology Outpatient Clinic. A thorough clinical examination was performed, including entheseal (Leeds enthesitis index (LEI)) and joint involvement (SJC/TJC 66/68). Patients were evaluated for pain and global disease activity on a visual analog scale (VAS) ranging from 0 to 100. This was followed by disease activity scores calculation: cDAPSA (Disease Activity Index for Psoriatic Arthritis) and Psoriasis Area and Severity Index (PASI). Serum oxylipins were determined by mass spectrometry and their association with clinical characteristics (PASI/LEI and cDAPSA) was analyzed using Metaboanalyst 4.0 and R version 3.6.1. Results Twenty PsO (average age 52 [10.8], 55% males) and 19 PsA patients (average age 60.5 [11.4], 63.1% males) were included. PsO patients had an average body mass index (BMI) of 33.7 (6.84) and an average PASI of 3.8 (4.2). PsA patients had an average BMI of 31.9 (5.6), TJC of 9.3 (10.41), SJC of 3.7 (4.23), with an average cDAPSA of 23.3 (11.4). 63.1% of PsA patients had enthesitis (average LEI 2.2 [3]) and the same percentage had psoriasis (average PASI 3(5]). Sera were analyzed for oxylipin levels. PsO and PsA patients with higher PASI score (> 2.5) had significantly lower serum concentrations of pro-inflammatory oxylipins, most of them arachidonic acid derived (AA). Oxylipin profiling did not associate with cDAPSA. Interestingly, several AA-derived oxylipins (5,15 di-HETE (5S,15S-dihydroxy-6E,8Z,10Z,13E-eicosatetraenoic acid), 5-oxoETE (5-Oxo-eicosatetraenoic acid), PGE2 (prostaglandin E2), 11bPGE2 (11 beta prostaglandin D2), and LTB4 (leukotriene B4)) were significantly increased in PsA patients with enthesitis compared to those without. Conclusions The AA-derived proinflammatory oxylipins were lower in both PsO and PsA patients with higher skin scores. Joint disease activity was not associated with the concentrations of oxylipins. Yet, enthesitis was associated with an increase of AA-derived pro-inflammatory oxylipins in PsA patients. Further studies are needed to determine whether oxylipin profiling can be a good biomarker of enthesitis in PsA patients. Supplementary Information The online version contains supplementary material available at 10.1186/s13075-021-02575-y.
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Affiliation(s)
- Roxana Coras
- Department of Medicine, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA. .,Autonomous University of Barcelona, Campus de la UAB, Plaça Cívica, 08193 Bellaterra, Barcelona, Spain.
| | - Arthur Kavanaugh
- Department of Medicine, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA
| | - Angela Kluzniak
- Department of Medicine, University of Rochester, Medical Center, 601 Elmwood Ave, Rochester, NY, 14642, USA
| | - Dustina Holt
- Department of Medicine, University of Rochester, Medical Center, 601 Elmwood Ave, Rochester, NY, 14642, USA
| | - Amy Weilgosz
- Department of Medicine, University of Rochester, Medical Center, 601 Elmwood Ave, Rochester, NY, 14642, USA
| | - Armando Aaron
- Department of Pharmacology, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA
| | - Oswald Quehenberger
- Department of Pharmacology, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA
| | - Christopher Ritchlin
- Department of Medicine, University of Rochester, Medical Center, 601 Elmwood Ave, Rochester, NY, 14642, USA
| | - Monica Guma
- Department of Medicine, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.,Autonomous University of Barcelona, Campus de la UAB, Plaça Cívica, 08193 Bellaterra, Barcelona, Spain
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Abstract
High levels of PGE2 have been implicated in the pathogenesis of intestinal inflammatory disorders such as necrotizing enterocolitis (NEC) and peritonitis. However, PGE2 has a paradoxical effect: its low levels promote intestinal homeostasis, whereas high levels may contribute to pathology. These concentration-dependent effects are mediated by four receptors, EP1-EP4. In this study, we evaluate the effect of blockade of the low affinity pro-inflammatory receptors EP1 and EP2 on expression of COX-2, the rate-limiting enzyme in PGE2 biosynthesis, and on gut barrier permeability using cultured enterocytes and three different models of intestinal injury. PGE2 upregulated COX-2 in IEC-6 enterocytes, and this response was blocked by the EP2 antagonist PF-04418948, but not by the EP1 antagonist ONO-8711 or EP4 antagonist E7046. In the neonatal rat model of NEC, EP2 antagonist and low dose of COX-2 inhibitor Celecoxib, but not EP1 antagonist, reduced NEC pathology as well as COX-2 mRNA and protein expression. In the adult mouse endotoxemia and cecal ligation/puncture models, EP2, but not EP1 genetic deficiency decreased COX-2 expression in the intestine. Our results indicate that the EP2 receptor plays a critical role in the positive feedback regulation of intestinal COX-2 by its end-product PGE2 during inflammation and may be a novel therapeutic target in the treatment of NEC.
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10
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Park HS, Choi S, Back YW, Lee KI, Choi HG, Kim HJ. Mycobacterium tuberculosis RpfE-Induced Prostaglandin E2 in Dendritic Cells Induces Th1/Th17 Cell Differentiation. Int J Mol Sci 2021; 22:ijms22147535. [PMID: 34299161 PMCID: PMC8304802 DOI: 10.3390/ijms22147535] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/05/2021] [Accepted: 07/11/2021] [Indexed: 01/13/2023] Open
Abstract
Prostaglandin E2 (PGE2) is an important biological mediator involved in the defense against Mycobacterium tuberculosis (Mtb) infection. Currently, there are no reports on the mycobacterial components that regulate PGE2 production. Previously, we have reported that RpfE-treated dendritic cells (DCs) effectively expanded the Th1 and Th17 cell responses simultaneously; however, the mechanism underlying Th1 and Th17 cell differentiation is unclear. Here, we show that PGE2 produced by RpfE-activated DCs via the MAPK and cyclooxygenase 2 signaling pathways induces Th1 and Th17 cell responses mainly via the EP4 receptor. Furthermore, mice administered intranasally with PGE2 displayed RpfE-induced antigen-specific Th1 and Th17 responses with a significant reduction in bacterial load in the lungs. Furthermore, the addition of optimal PGE2 amount to IL-2-IL-6-IL-23p19-IL-1β was essential for promoting differentiation into Th1/Th17 cells with strong bactericidal activity. These results suggest that RpfE-matured DCs produce PGE2 that induces Th1 and Th17 cell differentiation with potent anti-mycobacterial activity.
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11
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Sehanobish E, Asad M, Barbi M, Porcelli SA, Jerschow E. Aspirin Actions in Treatment of NSAID-Exacerbated Respiratory Disease. Front Immunol 2021; 12:695815. [PMID: 34305932 PMCID: PMC8297972 DOI: 10.3389/fimmu.2021.695815] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 06/07/2021] [Indexed: 12/21/2022] Open
Abstract
Non-steroidal Anti-inflammatory drugs (NSAID)-exacerbated respiratory disease (N-ERD) is characterized by nasal polyposis, chronic rhinosinusitis, adult-onset asthma and hypersensitive reactions to cyclooxygenase-1 (COX-1) inhibitors. Among the available treatments for this disease, a combination of endoscopic sinus surgery followed by aspirin desensitization and aspirin maintenance therapy has been an effective approach. Studies have shown that long-term aspirin maintenance therapy can reduce the rate of nasal polyp recurrence in patients with N-ERD. However, the exact mechanism by which aspirin can both trigger and suppress airway disease in N-ERD remains poorly understood. In this review, we summarize current knowledge of aspirin effects in N-ERD, cardiovascular disease, and cancer, and consider potential mechanistic pathways accounting for the effects of aspirin in N-ERD.
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Affiliation(s)
- Esha Sehanobish
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, United States
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Mohammad Asad
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, United States
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Mali Barbi
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Steven A. Porcelli
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, United States
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Elina Jerschow
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, United States
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, United States
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Sandgruber F, Gielsdorf A, Baur AC, Schenz B, Müller SM, Schwerdtle T, Stangl GI, Griehl C, Lorkowski S, Dawczynski C. Variability in Macro- and Micronutrients of 15 Commercially Available Microalgae Powders. Mar Drugs 2021; 19:md19060310. [PMID: 34071995 PMCID: PMC8228358 DOI: 10.3390/md19060310] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/22/2021] [Accepted: 05/24/2021] [Indexed: 11/17/2022] Open
Abstract
The nutrient composition of 15 commercially available microalgae powders of Arthrospira platensis, Chlorella pyrenoidosa and vulgaris, Dunaliella salina, Haematococcus pluvialis, Tetraselmis chuii, and Aphanizomenon flos-aquae was analyzed. The Dunaliella salina powders were characterized by a high content of carbohydrates, saturated fatty acids (SFAs), omega-6-polyunsaturated fatty acids (n6-PUFAs), heavy metals, and α-tocopherol, whereas the protein amounts, essential amino acids (EAAs), omega-3-PUFAs (n3-PUFAs), vitamins, and minerals were low. In the powder of Haematococcus pluvialis, ten times higher amounts of carotenoids compared to all other analyzed powders were determined, yet it was low in vitamins D and E, protein, and EAAs, and the n6/n3-PUFAs ratio was comparably high. Vitamin B12, quantified as cobalamin, was below 0.02 mg/100 g dry weight (d.w.) in all studied powders. Based on our analysis, microalgae such as Aphanizomenon and Chlorella may contribute to an adequate intake of critical nutrients such as protein with a high content of EAAs, dietary fibers, n3-PUFAs, Ca, Fe, Mg, and Zn, as well as vitamin D and E. Yet, the nutritional value of Aphanizomenon flos-aquae was slightly decreased by high contents of SFAs. The present data show that microalgae are rich in valuable nutrients, but the macro- and micronutrient profiles differ strongly between and within species.
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Affiliation(s)
- Fabian Sandgruber
- Junior Research Group Nutritional Concepts, Institute of Nutritional Science, Friedrich Schiller University Jena, Dornburger Str. 29, 07743 Jena, Germany; (F.S.); (B.S.)
- Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD) Jena-Halle-Leipzig, Dornburger Str. 25, 07743 Jena, Germany; (G.I.S.); (S.L.)
| | - Annekathrin Gielsdorf
- Competence Center Algal Biotechnology, Anhalt University of Applied Science, Bernburger Straße 55, 06366 Köthen, Germany; (A.G.); (C.G.)
| | - Anja C. Baur
- Institute of Agricultural and Nutritional Science, Martin Luther University Halle-Wittenberg, Theodor-Lieser-Str. 11, 06120 Halle, Germany;
| | - Benjamin Schenz
- Junior Research Group Nutritional Concepts, Institute of Nutritional Science, Friedrich Schiller University Jena, Dornburger Str. 29, 07743 Jena, Germany; (F.S.); (B.S.)
- Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD) Jena-Halle-Leipzig, Dornburger Str. 25, 07743 Jena, Germany; (G.I.S.); (S.L.)
| | - Sandra Marie Müller
- Department of Food Chemistry, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114–116, 14558 Nuthetal, Germany; (S.M.M.); (T.S.)
| | - Tanja Schwerdtle
- Department of Food Chemistry, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114–116, 14558 Nuthetal, Germany; (S.M.M.); (T.S.)
- NutriAct-Competence Cluster Nutrition Research, Berlin-Potsdam, Arthur-Scheunert-Allee 114–116, 14558 Nuthetal, Germany
| | - Gabriele I. Stangl
- Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD) Jena-Halle-Leipzig, Dornburger Str. 25, 07743 Jena, Germany; (G.I.S.); (S.L.)
- Institute of Agricultural and Nutritional Science, Martin Luther University Halle-Wittenberg, Theodor-Lieser-Str. 11, 06120 Halle, Germany;
| | - Carola Griehl
- Competence Center Algal Biotechnology, Anhalt University of Applied Science, Bernburger Straße 55, 06366 Köthen, Germany; (A.G.); (C.G.)
| | - Stefan Lorkowski
- Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD) Jena-Halle-Leipzig, Dornburger Str. 25, 07743 Jena, Germany; (G.I.S.); (S.L.)
- Institute of Nutritional Science, Friedrich Schiller University Jena, Dornburger Str. 25, 07743 Jena, Germany
| | - Christine Dawczynski
- Junior Research Group Nutritional Concepts, Institute of Nutritional Science, Friedrich Schiller University Jena, Dornburger Str. 29, 07743 Jena, Germany; (F.S.); (B.S.)
- Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD) Jena-Halle-Leipzig, Dornburger Str. 25, 07743 Jena, Germany; (G.I.S.); (S.L.)
- Correspondence: ; Tel.: +49-(3641)-9-49656
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Yadav P, Bhatt B, Balaji KN. Selective Activation of MST1/2 Kinases by Retinoid Agonist Adapalene Abrogates AURKA-Regulated Septic Arthritis. THE JOURNAL OF IMMUNOLOGY 2021; 206:2888-2899. [PMID: 34031150 DOI: 10.4049/jimmunol.2001360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 04/04/2021] [Indexed: 11/19/2022]
Abstract
Septic arthritis is a chronic inflammatory disorder caused by Staphylococcus aureus invasion of host synovium, which often progresses to impairment of joint functions. Although it is known that disease progression is intricately dependent on dysregulated inflammation of the knee joint, identification of molecular events mediating such imbalance during S. aureus-induced septic arthritis still requires detailed investigation. In this article, we report that Aurora kinase A (AURKA) responsive WNT signaling activates S. aureus infection-triggered septic arthritis, which results in inflammation of the synovium. In this context, treatment with adapalene, a synthetic retinoid derivative, in a mouse model for septic arthritis shows significant reduction of proinflammatory mediators with a simultaneous decrease in bacterial burden and prevents cartilage loss. Mechanistically, adapalene treatment inhibits WNT signaling with concomitant activation of HIPPO signaling, generating alternatively activated macrophages. Collectively, we establish adapalene as a promising strategy to suppress S. aureus-induced irreversible joint damage.
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Affiliation(s)
- Preeti Yadav
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India
| | - Bharat Bhatt
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India
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Knuplez E, Sturm EM, Marsche G. Emerging Role of Phospholipase-Derived Cleavage Products in Regulating Eosinophil Activity: Focus on Lysophospholipids, Polyunsaturated Fatty Acids and Eicosanoids. Int J Mol Sci 2021; 22:4356. [PMID: 33919453 PMCID: PMC8122506 DOI: 10.3390/ijms22094356] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/16/2021] [Accepted: 04/19/2021] [Indexed: 12/19/2022] Open
Abstract
Eosinophils are important effector cells involved in allergic inflammation. When stimulated, eosinophils release a variety of mediators initiating, propagating, and maintaining local inflammation. Both, the activity and concentration of secreted and cytosolic phospholipases (PLAs) are increased in allergic inflammation, promoting the cleavage of phospholipids and thus the production of reactive lipid mediators. Eosinophils express high levels of secreted phospholipase A2 compared to other leukocytes, indicating their direct involvement in the production of lipid mediators during allergic inflammation. On the other side, eosinophils have also been recognized as crucial mediators with regulatory and homeostatic roles in local immunity and repair. Thus, targeting the complex network of lipid mediators offer a unique opportunity to target the over-activation and 'pro-inflammatory' phenotype of eosinophils without compromising the survival and functions of tissue-resident and homeostatic eosinophils. Here we provide a comprehensive overview of the critical role of phospholipase-derived lipid mediators in modulating eosinophil activity in health and disease. We focus on lysophospholipids, polyunsaturated fatty acids, and eicosanoids with exciting new perspectives for future drug development.
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Affiliation(s)
| | | | - Gunther Marsche
- Otto Loewi Research Center, Division of Pharmacology, Medical University of Graz, 8010 Graz, Austria; (E.K.); (E.M.S.)
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Chmielińska M, Olesińska M, Romanowska-Próchnicka K, Szukiewicz D. Haptoglobin and Its Related Protein, Zonulin-What Is Their Role in Spondyloarthropathy? J Clin Med 2021; 10:jcm10051131. [PMID: 33800376 PMCID: PMC7962838 DOI: 10.3390/jcm10051131] [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: 02/14/2021] [Revised: 03/04/2021] [Accepted: 03/05/2021] [Indexed: 11/16/2022] Open
Abstract
Haptoglobin (Hp) is an acute phase protein which supports the immune response and protects tissues from free radicals. Its concentration correlates with disease activity in spondyloarthropathies (SpAs). The Hp polymorphism determines the functional differences between Hp1 and Hp2 protein products. The role of the Hp polymorphism has been demonstrated in many diseases. In particular, the Hp 2-2 phenotype has been associated with the unfavorable course of some inflammatory and autoimmune disorders. Its potential role in modulating the immune system in SpA is still unknown. This article contains pathophysiological considerations on the potential relationship between Hp, its polymorphism and SpA.
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Affiliation(s)
- Magdalena Chmielińska
- Department of Biophysics and Human Physiology, Medical University of Warsaw, Chałubińskiego 5, 02-004 Warsaw, Poland; (K.R.-P.); (D.S.)
- Department of Connective Tissue Diseases, National Institute of Geriatrics, Rheumatology and Rehabilitation, Spartańska 1, 02-637 Warsaw, Poland;
- Correspondence:
| | - Marzena Olesińska
- Department of Connective Tissue Diseases, National Institute of Geriatrics, Rheumatology and Rehabilitation, Spartańska 1, 02-637 Warsaw, Poland;
| | - Katarzyna Romanowska-Próchnicka
- Department of Biophysics and Human Physiology, Medical University of Warsaw, Chałubińskiego 5, 02-004 Warsaw, Poland; (K.R.-P.); (D.S.)
- Department of Connective Tissue Diseases, National Institute of Geriatrics, Rheumatology and Rehabilitation, Spartańska 1, 02-637 Warsaw, Poland;
| | - Dariusz Szukiewicz
- Department of Biophysics and Human Physiology, Medical University of Warsaw, Chałubińskiego 5, 02-004 Warsaw, Poland; (K.R.-P.); (D.S.)
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Tang M, Lu L, Yu X. Interleukin-17A Interweaves the Skeletal and Immune Systems. Front Immunol 2021; 11:625034. [PMID: 33613566 PMCID: PMC7890031 DOI: 10.3389/fimmu.2020.625034] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 12/23/2020] [Indexed: 02/06/2023] Open
Abstract
The complex crosstalk between the immune and the skeletal systems plays an indispensable role in the maintenance of skeletal homeostasis. Various cytokines are involved, including interleukin (IL)-17A. A variety of immune and inflammatory cells produces IL-17A, especially Th17 cells, a subtype of CD4+ T cells. IL-17A orchestrates diverse inflammatory and immune processes. IL-17A induces direct and indirect effects on osteoclasts. The dual role of IL-17A on osteoclasts partly depends on its concentrations and interactions with other factors. Interestingly, IL-17A exerts a dual role in osteoblasts in vitro. IL-17A is a bone-destroying cytokine in numerous immune-mediated bone diseases including postmenopausal osteoporosis (PMOP), rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondylarthritis (axSpA). This review will summarize and discuss the pathophysiological roles of IL-17A on the skeletal system and its potential strategies for application in immune-mediated bone diseases.
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Affiliation(s)
- Mengjia Tang
- Department of Endocrinology and Metabolism, Laboratory of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Lingyun Lu
- Department of Integrated Traditional Chinese and Western Medicine, Laboratory of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Xijie Yu
- Department of Endocrinology and Metabolism, Laboratory of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
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Dendritic Cells as a Disputed Fortress on the Tick-Host Battlefield. Trends Parasitol 2020; 37:340-354. [PMID: 33303363 DOI: 10.1016/j.pt.2020.11.004] [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: 08/19/2020] [Revised: 10/23/2020] [Accepted: 11/09/2020] [Indexed: 12/11/2022]
Abstract
From seminal publications in the early 1970s, the world learned that dendritic cells (DCs) are powerful and versatile antigen-presenting cells. It took a few years until the first studies expanded our understanding of the pivotal role of these immune 'soldiers' against ticks. Advances in biochemistry, molecular biology, and bioinformatics have shed light on the identification of key salivary molecules that modulate the biology of DCs in favor of tick parasitism. Here, we present a critical overview of the discoveries accumulated on the tick-host battlefield from a DC perspective. Moreover, the clinical significance of DC-targeted tick salivary components is discussed, not only as facilitators of the transmission of tick-borne pathogens or vaccine candidates, but also as potential immunobiologics to treat immune-mediated diseases.
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Norel X, Sugimoto Y, Ozen G, Abdelazeem H, Amgoud Y, Bouhadoun A, Bassiouni W, Goepp M, Mani S, Manikpurage HD, Senbel A, Longrois D, Heinemann A, Yao C, Clapp LH. International Union of Basic and Clinical Pharmacology. CIX. Differences and Similarities between Human and Rodent Prostaglandin E 2 Receptors (EP1-4) and Prostacyclin Receptor (IP): Specific Roles in Pathophysiologic Conditions. Pharmacol Rev 2020; 72:910-968. [PMID: 32962984 PMCID: PMC7509579 DOI: 10.1124/pr.120.019331] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Prostaglandins are derived from arachidonic acid metabolism through cyclooxygenase activities. Among prostaglandins (PGs), prostacyclin (PGI2) and PGE2 are strongly involved in the regulation of homeostasis and main physiologic functions. In addition, the synthesis of these two prostaglandins is significantly increased during inflammation. PGI2 and PGE2 exert their biologic actions by binding to their respective receptors, namely prostacyclin receptor (IP) and prostaglandin E2 receptor (EP) 1-4, which belong to the family of G-protein-coupled receptors. IP and EP1-4 receptors are widely distributed in the body and thus play various physiologic and pathophysiologic roles. In this review, we discuss the recent advances in studies using pharmacological approaches, genetically modified animals, and genome-wide association studies regarding the roles of IP and EP1-4 receptors in the immune, cardiovascular, nervous, gastrointestinal, respiratory, genitourinary, and musculoskeletal systems. In particular, we highlight similarities and differences between human and rodents in terms of the specific roles of IP and EP1-4 receptors and their downstream signaling pathways, functions, and activities for each biologic system. We also highlight the potential novel therapeutic benefit of targeting IP and EP1-4 receptors in several diseases based on the scientific advances, animal models, and human studies. SIGNIFICANCE STATEMENT: In this review, we present an update of the pathophysiologic role of the prostacyclin receptor, prostaglandin E2 receptor (EP) 1, EP2, EP3, and EP4 receptors when activated by the two main prostaglandins, namely prostacyclin and prostaglandin E2, produced during inflammatory conditions in human and rodents. In addition, this comparison of the published results in each tissue and/or pathology should facilitate the choice of the most appropriate model for the future studies.
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Affiliation(s)
- Xavier Norel
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Yukihiko Sugimoto
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Gulsev Ozen
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Heba Abdelazeem
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Yasmine Amgoud
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Amel Bouhadoun
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Wesam Bassiouni
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Marie Goepp
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Salma Mani
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Hasanga D Manikpurage
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Amira Senbel
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Dan Longrois
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Akos Heinemann
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Chengcan Yao
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Lucie H Clapp
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
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19
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Lee KMC, Zhang Z, Achuthan A, Fleetwood AJ, Smith JE, Hamilton JA, Cook AD. IL-23 in arthritic and inflammatory pain development in mice. Arthritis Res Ther 2020; 22:123. [PMID: 32471485 PMCID: PMC7345543 DOI: 10.1186/s13075-020-02212-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 05/06/2020] [Indexed: 12/12/2022] Open
Abstract
Background The cytokine, interleukin-23 (IL-23), can be critical for the progression of inflammatory diseases, including arthritis, and is often associated with T lymphocyte biology. We previously showed that certain lymphocyte-independent, inflammatory arthritis and pain models have a similar requirement for tumour necrosis factor (TNF), granulocyte macrophage-colony stimulating factor (GM-CSF), and C-C motif ligand 17 (CCL17). Given this correlation in cytokine requirements, we explored whether IL-23 might interact with this cytokine cluster in the control of arthritic and inflammatory pain. Methods The role of IL-23 in the development of pain-like behaviour was investigated using mouse arthritis models (zymosan-induced arthritis and GM-CSF-, TNF-, and CCL17-driven monoarticular arthritis) and inflammatory pain models (intraplantar zymosan, GM-CSF, TNF, and CCL17). Additionally, IL-23-induced inflammatory pain was measured in GM-CSF−/−, Tnf−/−, and Ccl17E/E mice and in the presence of indomethacin. Pain-like behaviour and arthritis were assessed by relative weight distribution in hindlimbs and histology, respectively. Cytokine mRNA expression in knees and paw skin was analysed by quantitative PCR. Blood and synovial cell populations were analysed by flow cytometry. Results We report, using Il23p19−/− mice, that innate immune (zymosan)-driven arthritic pain-like behaviour (herein referred to as pain) was completely dependent upon IL-23; optimal arthritic disease development required IL-23 (P < 0.05). Zymosan-induced inflammatory pain was also completely dependent on IL-23. In addition, we found that exogenous TNF-, GM-CSF-, and CCL17-driven arthritic pain, as well as inflammatory pain driven by each of these cytokines, were absent in Il23p19−/− mice; optimal disease in these mBSA-primed models was dependent on IL-23 (P < 0.05). Supporting this cytokine connection, it was found conversely that IL-23 (200 ng) can induce inflammatory pain at 4 h (P < 0.0001) with a requirement for each of the other cytokines as well as cyclooxygenase activity. Conclusions These findings indicate a role for IL-23 in innate immune-mediated arthritic and inflammatory pain with potential links to TNF, GM-CSF, CCL17, and eicosanoid function.
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Affiliation(s)
- Kevin M-C Lee
- Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, 3050, Australia.
| | - Zihao Zhang
- Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, 3050, Australia
| | - Adrian Achuthan
- Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, 3050, Australia
| | - Andrew J Fleetwood
- Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, 3050, Australia
| | - Julia E Smith
- Adaptive Immunity, GSK Medicines Research Centre, Stevenage, Hertfordshire, UK
| | - John A Hamilton
- Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, 3050, Australia.,Australian Institute for Musculoskeletal Science (AIMSS), The University of Melbourne and Western Health, St. Albans, Victoria, Australia
| | - Andrew D Cook
- Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, 3050, Australia
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20
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Du B, Zhu M, Li Y, Li G, Xi X. The prostaglandin E2 increases the production of IL-17 and the expression of costimulatory molecules on γδ T cells in rheumatoid arthritis. Scand J Immunol 2020; 91:e12872. [PMID: 32048307 DOI: 10.1111/sji.12872] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 02/05/2020] [Accepted: 02/09/2020] [Indexed: 12/12/2022]
Abstract
γδ T cells play important roles in the development of rheumatoid arthritis (RA) through their antigen-presenting capacity, release of pro-inflammatory cytokines, immunomodulatory properties, interaction with CD4+ CD25+ Tregs and promotion of antibody production by helping B cells. Although prostaglandin E2 (PGE2) was proved to have the ability to enhance the antigen-presenting function of dendritic cells and IL-17 production of CD4+ αβ T cells in RA, the role of PGE2 in γδ T cells from RA disease has not yet been clarified. The goal of this study was to determine the role of PGE2 in γδ T cells in RA. We first demonstrated that the population of γδT17 cells increased in patients with RA compared to healthy controls. Then, IL-17A level in patients with RA was shown to increase compared to healthy controls. After adding PGE2 to γδ T cells from patients with RA, the IL-17A level increased accordingly, and the expression of the costimulatory molecules, CD80 and CD86, on these cells also increased. These results suggest that PEG2 can increase the production of IL-17A and the expression of CD80 and CD86 on γδ T cells in patients with RA. These findings will benefit to explore new therapeutic targets for RA disease.
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Affiliation(s)
- Boyu Du
- Institute of Basic Medical Science, Hubei University of Medicine, Shiyan, China.,Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, China
| | - Min Zhu
- Institute of Basic Medical Science, Hubei University of Medicine, Shiyan, China
| | - Youling Li
- Renmin Hospital, Hubei University of Medicine, Shiyan, China
| | - Gang Li
- Renmin Hospital, Hubei University of Medicine, Shiyan, China
| | - Xueyan Xi
- Institute of Basic Medical Science, Hubei University of Medicine, Shiyan, China.,Renmin Hospital, Hubei University of Medicine, Shiyan, China.,Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, China
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21
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Amaradhi R, Banik A, Mohammed S, Patro V, Rojas A, Wang W, Motati DR, Dingledine R, Ganesh T. Potent, Selective, Water Soluble, Brain-Permeable EP2 Receptor Antagonist for Use in Central Nervous System Disease Models. J Med Chem 2020; 63:1032-1050. [PMID: 31904232 PMCID: PMC7394479 DOI: 10.1021/acs.jmedchem.9b01218] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Activation of prostanoid EP2 receptor exacerbates neuroinflammatory and neurodegenerative pathology in central nervous system diseases such as epilepsy, Alzheimer's disease, and cerebral aneurysms. A selective and brain-permeable EP2 antagonist will be useful to attenuate the inflammatory consequences of EP2 activation and to reduce the severity of these chronic diseases. We recently developed a brain-permeable EP2 antagonist 1 (TG6-10-1), which displayed anti-inflammatory and neuroprotective actions in rodent models of status epilepticus. However, this compound exhibited moderate selectivity to EP2, a short plasma half-life in rodents (1.7 h) and low aqueous solubility (27 μM), limiting its use in animal models of chronic disease. With lead-optimization studies, we have developed several novel EP2 antagonists with improved water solubility, brain penetration, high EP2 potency, and selectivity. These novel inhibitors suppress inflammatory gene expression induced by EP2 receptor activation in a microglial cell line, reinforcing the use of EP2 antagonists as anti-inflammatory agents.
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Affiliation(s)
- Radhika Amaradhi
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 1510 Clifton Rd; Atlanta, GA, 30322, United States of America
| | - Avijit Banik
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 1510 Clifton Rd; Atlanta, GA, 30322, United States of America
| | - Shabber Mohammed
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 1510 Clifton Rd; Atlanta, GA, 30322, United States of America
| | - Vidyavathi Patro
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 1510 Clifton Rd; Atlanta, GA, 30322, United States of America
| | - Asheebo Rojas
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 1510 Clifton Rd; Atlanta, GA, 30322, United States of America
| | - Wenyi Wang
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 1510 Clifton Rd; Atlanta, GA, 30322, United States of America
| | - Damoder Reddy Motati
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 1510 Clifton Rd; Atlanta, GA, 30322, United States of America
| | - Ray Dingledine
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 1510 Clifton Rd; Atlanta, GA, 30322, United States of America
| | - Thota Ganesh
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 1510 Clifton Rd; Atlanta, GA, 30322, United States of America
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22
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Zhang C, Wang L, Li T, Mao W, Liu B, Cao J. EP2/4 Receptors Promote the Synthesis of PGE 2 Increasing Tissue Damage in Bovine Endometrial Explants Induced by Escherichia coli. J Pharmacol Exp Ther 2020; 372:175-184. [PMID: 31732699 DOI: 10.1124/jpet.119.262444] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 11/11/2019] [Indexed: 12/17/2022] Open
Abstract
The bovine uterine is easily contaminated with bacteria during coitus or parturition. A previous study suggested that prostaglandin E2 (PGE2) promoted Escherichia coli-infected bovine endometrial tissue inflammatory damage via cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1). However, it remains unclear which PGE2 receptors regulate the proinflammatory effect of PGE2 In this study, we evaluated the effect of PGE2 and its mediated receptors on E. coli-infected endometrium explants isolated from the bovine uterus. The E. coli-infected bovine endometrial explants were cultured in vitro, and the study used EP2/4 receptor agonists to investigate the responses of COX-2, mPGES-1, PGE2, proinflammatory factors, and damage-associated molecular patterns (DAMPs). The expression of COX-2, mPGES-1, PGE2, proinflammatory factors, and DAMPs was significantly increased after infection with E. coli; however, the high expression levels caused by E. coli were reduced following treatment with COX-2 and mPGES-1 inhibitors. In addition, the expression levels of COX-2, mPGES-1, PGE2, proinflammatory factors, and DAMPs were higher in treatment with EP2/4 receptor agonists in E. coli-infected endometrium explants, and their promotable effects were effectively blocked by EP2/4 receptor antagonists. These findings provide evidence that PGE2 may promote the progress of inflammation in endometrial explants infected with E. coli in bovines. Furthermore, EP2/4 may be involved in a positive feedback loop for COX-2 and mPGES-1 expression, and this may be responsible for the proinflammatory reaction of PGE2 in E. coli-infected uteri of bovines. SIGNIFICANCE STATEMENT: PGE2 promoted E. coli-infected bovine endometrial tissue damage via COX-2 and mPGES-1. However, this proinflammatory effect of PGE2 depends on which receptors are affected by PGE2, and this remains unclear. In this study, it was investigated that EP2 and EP4 may be involved in a positive feedback loop for COX-2 and mPGES-1 expression, and this may be responsible for the proinflammatory reaction of PGE2 in E. coli-infected uteri of bovines.
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Affiliation(s)
- Chao Zhang
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine (C.Z., L.W., T.L., W.M., B.L., J.C.), and Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture (C.Z., L.W., T.L., W.M., B.L., J.C.), Inner Mongolia Agricultural University, Huhhot, China
| | - Lingrui Wang
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine (C.Z., L.W., T.L., W.M., B.L., J.C.), and Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture (C.Z., L.W., T.L., W.M., B.L., J.C.), Inner Mongolia Agricultural University, Huhhot, China
| | - Tingting Li
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine (C.Z., L.W., T.L., W.M., B.L., J.C.), and Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture (C.Z., L.W., T.L., W.M., B.L., J.C.), Inner Mongolia Agricultural University, Huhhot, China
| | - Wei Mao
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine (C.Z., L.W., T.L., W.M., B.L., J.C.), and Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture (C.Z., L.W., T.L., W.M., B.L., J.C.), Inner Mongolia Agricultural University, Huhhot, China
| | - Bo Liu
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine (C.Z., L.W., T.L., W.M., B.L., J.C.), and Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture (C.Z., L.W., T.L., W.M., B.L., J.C.), Inner Mongolia Agricultural University, Huhhot, China
| | - Jinshan Cao
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine (C.Z., L.W., T.L., W.M., B.L., J.C.), and Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture (C.Z., L.W., T.L., W.M., B.L., J.C.), Inner Mongolia Agricultural University, Huhhot, China
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23
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Abstract
While glucocorticoids have been used for over 50 years to treat rheumatoid and osteoarthritis pain, the prescription of glucocorticoids remains controversial because of potentially harmful side effects at the molecular, cellular and tissue levels. One member of the glucocorticoid family, dexamethasone (DEX) has recently been demonstrated to rescue cartilage matrix loss and chondrocyte viability in animal studies and cartilage explant models of tissue injury and post-traumatic osteoarthritis, suggesting the possibility of DEX as a disease-modifying drug if used appropriately. However, the literature on the effects of DEX on cartilage reveals conflicting results on the drug's safety, depending on the dose and duration of DEX exposure as well as the model system used. Overall, DEX has been shown to protect against arthritis-related changes in cartilage structure and function, including matrix loss, inflammation and cartilage viability. These beneficial effects are not always observed in model systems using initially healthy cartilage or isolated chondrocytes, where many studies have reported significant increases in chondrocyte apoptosis. It is crucially important to understand under what conditions DEX may be beneficial or harmful to cartilage and other joint tissues and to determine potential for safe use of this glucocorticoid in the clinic as a disease-modifying drug.
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Affiliation(s)
- R. Black
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - A. J. Grodzinsky
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA,Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA,Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA,Address for correspondence: Prof. Al Grodzinsky, MIT, Centre for Biomedical Engineering, 500 Technology Square, Cambridge, MA, 02139, USA.
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24
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Maseda D, Ricciotti E, Crofford LJ. Prostaglandin regulation of T cell biology. Pharmacol Res 2019; 149:104456. [PMID: 31553935 DOI: 10.1016/j.phrs.2019.104456] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 08/06/2019] [Accepted: 09/13/2019] [Indexed: 12/26/2022]
Abstract
Prostaglandins (PG) are pleiotropic bioactive lipids involved in the control of many physiological processes, including key roles in regulating inflammation. This links PG to the modulation of the quality and magnitude of immune responses. T cells, as a core part of the immune system, respond readily to inflammatory cues from their environment, and express a diverse array of PG receptors that contribute to their function and phenotype. Here we put in context our knowledge about how PG affect T cell biology, and review advances that bring light into how specific T cell functions that have been newly discovered are modulated through PG. We will also comment on drugs that target PG metabolism and sensing, their effect on T cell function during disease, and we will finally discuss how we can design new approaches that modulate PG in order to maximize desired therapeutic T cell effects.
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Affiliation(s)
- Damian Maseda
- Department of Microbiology, University of Pennsylvania School of Medicine, 8-138 Smillow Center for Translational Research, Philadelphia, PA, USA.
| | - Emanuela Ricciotti
- Department of Systems Pharmacology and Translational Therapeutics, Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, USA
| | - Leslie J Crofford
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
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25
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Venugopal N, Acharya P, Zarei M, Talahalli RR. Cysteinyl leukotriene receptor antagonism: a promising pharmacological strategy for lowering the severity of arthritis. Inflammopharmacology 2019; 27:923-931. [PMID: 31309487 DOI: 10.1007/s10787-019-00618-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 06/24/2019] [Indexed: 12/29/2022]
Abstract
BACKGROUND AND AIMS Though cyclooxygenase inhibitors are employed in rheumatoid arthritis treatment, modulators of leukotrienes are underexplored. We investigated the therapeutic potential of montelukast, a known cysteinyl leukotriene receptor-1 (CysLT1) inhibitor in an experimental rat model of arthritis. METHODS Arthritis was induced in rats, and montelukast (5 mg/kg body wt.) was administered prophylactically (PAM) and therapeutically (TAM) through oral route. RESULTS AND DISCUSSION Blood and joint tissue markers of oxidative stress (lipid peroxidation, protein carbonyls, and nitric oxides) were significantly (p < 0.05) reduced in montelukast administered rats. Paw inflammation, RA markers (RF and CRP), eicosanoids (PGE2, LTB4, and LTC4), cytokines (IL-1β and MCP-1), activity of hydrolytic enzymes (collagenase, elastase, and hyaluronidase), expression of matrix metalloproteinases (MMP), and EP-4 receptor were significantly (p < 0.05) reduced in montelukast administered rats. This study established that leukotriene inhibition through montelukast lowered the severity of arthritis and thus a potential strategy for reducing the severity of arthritis.
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Affiliation(s)
- Nayana Venugopal
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, Karnataka, 570020, India
| | - Pooja Acharya
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, Karnataka, 570020, India
| | - Mehrdad Zarei
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, Karnataka, 570020, India
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26
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Duchez AC, Boudreau LH, Naika GS, Rousseau M, Cloutier N, Levesque T, Gelb MH, Boilard E. Respective contribution of cytosolic phospholipase A2α and secreted phospholipase A 2 IIA to inflammation and eicosanoid production in arthritis. Prostaglandins Other Lipid Mediat 2019; 143:106340. [PMID: 31129176 DOI: 10.1016/j.prostaglandins.2019.106340] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 05/11/2019] [Accepted: 05/15/2019] [Indexed: 12/30/2022]
Abstract
Phospholipase A2s (PLA2) play a key role in generation of eicosanoids. Cytosolic PLA2α (cPLA2α) is constitutively expressed in most cells, whereas IIA secreted PLA2 (sPLA2-IIA) is induced during inflammation and is present at high levels in the synovial fluid of rheumatoid arthritis patients. In mice, both cPLA2α and sPLA2-IIA have been implicated in autoimmune arthritis; however, the respective contribution of these two enzymes to the pathogenesis and production of eicosanoids is unknown. We evaluated the respective role of cPLA2α and sPLA2-IIA with regard to arthritis and eicosanoid profile in an in vivo model of arthritis. While arthritis was most severe in mice expressing both enzymes, it was abolished when both cPLA2α and sPLA2-IIA were lacking. cPLA2α played a dominant role in the severity of arthritis, although sPLA2-IIA sufficed to significantly contribute to the disease. Several eicosanoids were modulated during the course of arthritis and numerous species involved sPLA2-IIA expression. This study confirms the critical role of PLA2s in arthritis and unveils the distinct contribution of cPLA2α and sPLA2-IIA to the eicosanoid profile in arthritis.
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Affiliation(s)
- Anne-Claire Duchez
- Centre de Recherche du Centre Hospitalier Universitaire de Québec, Faculté de Médecine de l'Université Laval, Département de microbiologie et immunologie, Québec, QC, G1V 4G2, Canada
| | - Luc H Boudreau
- Centre de Recherche du Centre Hospitalier Universitaire de Québec, Faculté de Médecine de l'Université Laval, Département de microbiologie et immunologie, Québec, QC, G1V 4G2, Canada; Department of Chemistry and Biochemistry, Université de Moncton, Moncton, E1A 3E9, Canada
| | - Gajendra S Naika
- Department of Chemistry, University of Washington, Seattle, WA, 98195, USA
| | - Matthieu Rousseau
- Centre de Recherche du Centre Hospitalier Universitaire de Québec, Faculté de Médecine de l'Université Laval, Département de microbiologie et immunologie, Québec, QC, G1V 4G2, Canada
| | - Nathalie Cloutier
- Centre de Recherche du Centre Hospitalier Universitaire de Québec, Faculté de Médecine de l'Université Laval, Département de microbiologie et immunologie, Québec, QC, G1V 4G2, Canada
| | - Tania Levesque
- Centre de Recherche du Centre Hospitalier Universitaire de Québec, Faculté de Médecine de l'Université Laval, Département de microbiologie et immunologie, Québec, QC, G1V 4G2, Canada
| | - Michael H Gelb
- Department of Chemistry, University of Washington, Seattle, WA, 98195, USA
| | - Eric Boilard
- Centre de Recherche du Centre Hospitalier Universitaire de Québec, Faculté de Médecine de l'Université Laval, Département de microbiologie et immunologie, Québec, QC, G1V 4G2, Canada; Canadian National Transplantation Research Program, Edmonton, Alberta, Canada.
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Martin EM, Schirmer JM, Jones SL, Davis JL. Pharmacokinetics and ex vivo anti-inflammatory effects of oral misoprostol in horses. Equine Vet J 2019; 51:415-421. [PMID: 30256450 PMCID: PMC6587934 DOI: 10.1111/evj.13024] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 08/14/2018] [Accepted: 09/18/2018] [Indexed: 01/09/2023]
Abstract
BACKGROUND Misoprostol is an E prostanoid (EP) 2, 3 and 4 receptor agonist that is anecdotally used to treat and prevent NSAID-induced GI injury in horses. Misoprostol elicits anti-inflammatory effects in vivo in men and rodents, and inhibits TNFα production in equine leucocytes in vitro. OBJECTIVE Define the pharmacokinetic parameters of oral misoprostol in horses, and determine the inhibitory effect of oral misoprostol administration on equine leucocyte TNFα production in an ex vivo inflammation model. STUDY DESIGN Pharmacokinetic study, ex vivo experimental study. METHODS Six healthy adult horses of mixed breeds were used. In phase one, horses were given 5 μg/kg misoprostol orally, and blood was collected at predetermined times for determination of misoprostol free acid (MFA) by UHPLC-MS/MS. Pharmacokinetic parameters were calculated. In phase two, horses were dosed as in phase one, and blood was collected at T0, 0.5, 1 and 4 h following misoprostol administration for leucocyte isolation. Leucocytes were stimulated with 100 ng/mL LPS, and TNFα mRNA concentrations were determined via quantitative real-time PCR. RESULTS About 5 μg/kg oral misoprostol produced a rapid time to maximum concentration (Tmax ) of 23.4 ± 2.4 min, with a maximum concentration (Cmax ) of 0.29 ± 0.07 ng/mL and area under the curve (AUC0-∞ ) of 0.4 ± 0.12 h ng/mL. LPS stimulation of equine leucocytes ex vivo significantly increased TNFα mRNA concentrations, and there was no significant effect of misoprostol even at the Tmax . MAIN LIMITATIONS Only a single dose was used, and sample size was small. CONCLUSIONS Misoprostol is rapidly absorbed following oral administration in horses, and a single 5 μg/kg dose had no significant inhibitory effect on ex vivo LPS-stimulated TNFα mRNA production in leucocytes. Further studies analysing different dosing strategies, including repeat administration or combination with other anti-inflammatory drugs, are warranted.
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Affiliation(s)
- E. M. Martin
- North Carolina State University College of Veterinary MedicineRaleighNorth CarolinaUSA
| | - J. M. Schirmer
- North Carolina State University College of Veterinary MedicineRaleighNorth CarolinaUSA
| | - S. L. Jones
- North Carolina State University College of Veterinary MedicineRaleighNorth CarolinaUSA
| | - J. L. Davis
- VA‐MD College of Veterinary MedicineBlacksburgVirginiaUSA
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Arioka M, Takahashi-Yanaga F. Glycogen synthase kinase-3 inhibitor as a multi-targeting anti-rheumatoid drug. Biochem Pharmacol 2019; 165:207-213. [PMID: 30776323 DOI: 10.1016/j.bcp.2019.02.020] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 02/14/2019] [Indexed: 01/01/2023]
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory joint disease that causes swelling, bone erosion, and joint disorder. Patients with RA therefore suffer from pain and physiological disability, and have a decreased quality of life. During the progression of RA, many different types of cells and inflammatory factors influence each other with an important role. A better understanding of the pathology of RA should therefore lead to the development of effective anti-rheumatoid drugs, such as the anti-TNFα antibody. Glycogen synthase kinase-3 (GSK-3) is a cytoplasmic serine/threonine protein kinase that is involved in a large number of key cellular processes and is dysregulated in a wide variety of diseases, including inflammation and osteoporosis. The accumulated evidence has suggested that GSK-3 could be involved in multiple steps in the progression of RA. In the present review, the mechanisms of the pathogenesis of RA are summarized, and recent developments and potential new drugs targeting GSK-3 are discussed.
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Affiliation(s)
- Masaki Arioka
- Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Fumi Takahashi-Yanaga
- Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
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29
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Yao C, Narumiya S. Prostaglandin-cytokine crosstalk in chronic inflammation. Br J Pharmacol 2019; 176:337-354. [PMID: 30381825 PMCID: PMC6329627 DOI: 10.1111/bph.14530] [Citation(s) in RCA: 160] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2018] [Revised: 10/13/2018] [Accepted: 10/17/2018] [Indexed: 12/28/2022] Open
Abstract
Chronic inflammation underlies various debilitating disorders including autoimmune, neurodegenerative, vascular and metabolic diseases as well as cancer, where aberrant activation of the innate and acquired immune systems is frequently seen. Since non-steroidal anti-inflammatory drugs exert their effects by inhibiting COX and suppressing PG biosynthesis, PGs have been traditionally thought to function mostly as mediators of acute inflammation. However, an inducible COX isoform, COX-2, is often highly expressed in tissues of the chronic disorders, suggesting an as yet unidentified role of PGs in chronic inflammation. Recent studies have shown that in addition to their short-lived actions in acute inflammation, PGs crosstalk with cytokines and amplify the cytokine actions on various types of inflammatory cells and drive pathogenic conversion of these cells by critically regulating their gene expression. One mode of such PG-mediated amplification is to induce the expression of relevant cytokine receptors, which is typically observed in Th1 cell differentiation and Th17 cell expansion, events leading to chronic immune inflammation. Another mode of amplification is cooperation of PGs with cytokines at the transcription level. Typically, PGs and cytokines synergistically activate NF-κB to induce the expression of inflammation-related genes, one being COX-2 itself, which makes PG-mediated positive feedback loops. This signalling consequently enhances the expression of various NF-κB-induced genes including chemokines to macrophages and neutrophils, which enables sustained infiltration of these cells and further amplifies chronic inflammation. In addition, PGs are also involved in tissue remodelling such as fibrosis and angiogenesis. In this article, we review these findings and discuss their relevance to human diseases.
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Affiliation(s)
- Chengcan Yao
- Centre for Inflammation Research, Queen's Medical Research InstituteThe University of EdinburghEdinburghUK
| | - Shuh Narumiya
- Alliance Laboratory for Advanced Medical Research and Department of Drug Discovery Medicine, Medical Innovation CenterKyoto University Graduate School of MedicineKyotoJapan
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Feuerherm AJ, Dennis EA, Johansen B. Cytosolic group IVA phospholipase A2 inhibitors, AVX001 and AVX002, ameliorate collagen-induced arthritis. Arthritis Res Ther 2019; 21:29. [PMID: 30665457 PMCID: PMC6341602 DOI: 10.1186/s13075-018-1794-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Accepted: 12/11/2018] [Indexed: 02/08/2023] Open
Abstract
Background Cytosolic phospholipase A2 group IVA (cPLA2α)-deficient mice are resistant to collagen-induced arthritis, suggesting that cPLA2α is an important therapeutic target. Here, the anti-inflammatory effects of the AVX001 and AVX002 cPLA2α inhibitors were investigated. Methods In vitro enzyme activity was assessed by a modified Dole assay. Effects on inhibiting IL-1β-induced release of arachidonic acid (AA) and prostaglandin E2 (PGE2) were measured using SW982 synoviocyte cells. In vivo effects were studied in prophylactic and therapetic murine collagen-induced arthritis models and compared to methotrexate (MTX) and Enbrel, commonly used anti-rheumatic drugs. The in vivo response to treatment was evaluated in terms of the arthritis index (AI), histopathology scores and by plasma levels of PGE2 following 14 and 21 days of treatment. Results Both cPLA2α inhibitors are potent inhibitors of cPLA2α in vitro. In synoviocytes, AVX001 and AVX002 reduce, but do not block, release of AA or PGE2 synthesis. In both CIA models, the AI and progression of arthritis were significantly lower in the mice treated with AVX001, AVX002, Enbrel and MTX than in non- treated mice. Several histopathology parameters of joint damage were found to be significantly reduced by AVX001 and AVX002 in both prophylactic and therapeutic study modes; namely articular cavity and peripheral tissue inflammatory cell infiltration; capillary and synovial hyperplasia; articular cartilage surface damage; and periostal and endochondral ossification. In comparison, MTX did not significantly improve any histopathology parameters and Enbrel only improved ossification. Finally, as a biomarker of inflammation and as an indication that AVX001 and AVX002 blocked the cPLA2α target, we determined that plasma levels of PGE2 were significantly reduced in response to the AVX inhibitors and MTX, but not Enbrel. Conclusions AVX001 and AVX002 display potent anti-inflammatory activity and disease-modifying properties in cellular and in vivo models. The in vivo effects of AVX001 and AVX002 were comparable to, or superior, to those of MTX and Enbrel. Taken together, this study suggests that cPLA2α inhibitors AVX001 and AVX002 are promising small molecule disease-modifying anti-rheumatic therapies.
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Affiliation(s)
- A J Feuerherm
- Department of Biology, Norwegian University of Science and Technology, N-7491, Trondheim, Norway
| | - E A Dennis
- Department of Chemistry and Biochemistry, University of California-San Diego, La Jolla, California, 92093-0601, USA.,Department of Pharmacology, School of Medicine, University of California-San Diego, La Jolla, California, 92093-0601, USA
| | - B Johansen
- Department of Biology, Norwegian University of Science and Technology, N-7491, Trondheim, Norway.
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31
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Ganesh T, Banik A, Dingledine R, Wang W, Amaradhi R. Peripherally Restricted, Highly Potent, Selective, Aqueous-Soluble EP2 Antagonist with Anti-Inflammatory Properties. Mol Pharm 2018; 15:5809-5817. [PMID: 30398879 DOI: 10.1021/acs.molpharmaceut.8b00764] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The prostaglandin E2 receptor, EP2, plays an important role in physiology and in a variety of pathological conditions. Studies indicate that EP2 is pro-inflammatory in chronic peripheral and central nervous system disease and cancer models. Thus, targeting the EP2 receptor with small molecules could be a therapeutic strategy for treating inflammatory diseases and cancer. We recently reported a novel class of competitive antagonists of the EP2 receptor. However, earlier leads displayed low selectivity against the DP1 prostanoid receptor, moderate plasma half-life, and low aqueous solubility, which renders them suboptimal for testing in animal models of disease. We now report a novel compound TG8-69, which has suitable drug-like properties. We present synthesis, lead-optimization studies, pharmacological characterization, and anti-inflammatory properties of this compound that support its use in chronic peripheral inflammatory diseases, including rheumatoid arthritis, endometriosis, and cancer, in which EP2 appears to play a pathogenic role.
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Affiliation(s)
- Thota Ganesh
- Department of Pharmacology, School of Medicine , Emory University , 1510 Clifton Rd , Atlanta , Georgia 30322 , United States
| | - Avijit Banik
- Department of Pharmacology, School of Medicine , Emory University , 1510 Clifton Rd , Atlanta , Georgia 30322 , United States
| | - Ray Dingledine
- Department of Pharmacology, School of Medicine , Emory University , 1510 Clifton Rd , Atlanta , Georgia 30322 , United States
| | - Wenyi Wang
- Department of Pharmacology, School of Medicine , Emory University , 1510 Clifton Rd , Atlanta , Georgia 30322 , United States
| | - Radhika Amaradhi
- Department of Pharmacology, School of Medicine , Emory University , 1510 Clifton Rd , Atlanta , Georgia 30322 , United States
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van Tok MN, Na S, Lao CR, Alvi M, Pots D, van de Sande MGH, Taurog JD, Sedgwick JD, Baeten DL, van Duivenvoorde LM. The Initiation, but Not the Persistence, of Experimental Spondyloarthritis Is Dependent on Interleukin-23 Signaling. Front Immunol 2018; 9:1550. [PMID: 30038617 PMCID: PMC6046377 DOI: 10.3389/fimmu.2018.01550] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Accepted: 06/22/2018] [Indexed: 12/30/2022] Open
Abstract
IL-17A is a central driver of spondyloarthritis (SpA), its production was originally proposed to be IL-23 dependent. Emerging preclinical and clinical evidence suggests, however, that IL-17A and IL-23 have a partially overlapping but distinct biology. We aimed to assess the extent to which IL-17A-driven pathology is IL-23 dependent in experimental SpA. Experimental SpA was induced in HLA-B27/Huβ2m transgenic rats, followed by prophylactic or therapeutic treatment with an anti-IL23R antibody or vehicle control. Spondylitis and arthritis were scored clinically and hind limb swelling was measured. Draining lymph node cytokine expression levels were analyzed directly ex vivo, and IL-17A protein was measured upon restimulation with PMA/ionomycin. Prophylactic treatment with anti-IL23R completely protected against the development of both spondylitis and arthritis, while vehicle-treated controls did develop spondylitis and arthritis. In a therapeutic study, anti-IL23R treatment failed to reduce the incidence or decrease the severity of experimental SpA. Mechanistically, expression of downstream effector cytokines, including IL-17A and IL-22, was significantly suppressed in anti-IL23R versus vehicle-treated rats in the prophylactic experiments. Accordingly, the production of IL-17A upon restimulation was reduced. In contrast, there was no difference in IL-17A and IL-22 expression after therapeutic anti-IL23R treatment. Targeting the IL-23 axis during the initiation phase of experimental SpA-but not in established disease-inhibits IL-17A expression and suppresses disease, suggesting the existence of IL-23-independent IL-17A production. Whether IL-17A can be produced independent of IL-23 in human SpA remains to be established.
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Affiliation(s)
- Melissa N van Tok
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Academic Medical Center/University of Amsterdam, Amsterdam, Netherlands.,Department of Experimental Immunology, Academic Medical Center/University of Amsterdam, Amsterdam, Netherlands
| | - Songqing Na
- Eli Lilly and Co, San Diego, CA, United States
| | | | - Marina Alvi
- Eli Lilly and Co, San Diego, CA, United States
| | - Desirée Pots
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Academic Medical Center/University of Amsterdam, Amsterdam, Netherlands.,Department of Experimental Immunology, Academic Medical Center/University of Amsterdam, Amsterdam, Netherlands
| | - Marleen G H van de Sande
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Academic Medical Center/University of Amsterdam, Amsterdam, Netherlands.,Department of Experimental Immunology, Academic Medical Center/University of Amsterdam, Amsterdam, Netherlands
| | - Joel D Taurog
- Rheumatic Diseases Division, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, United States
| | - Jonathon D Sedgwick
- Eli Lilly and Co, San Diego, CA, United States.,Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, United States
| | - Dominique L Baeten
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Academic Medical Center/University of Amsterdam, Amsterdam, Netherlands.,Department of Experimental Immunology, Academic Medical Center/University of Amsterdam, Amsterdam, Netherlands
| | - Leonie M van Duivenvoorde
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Academic Medical Center/University of Amsterdam, Amsterdam, Netherlands.,Department of Experimental Immunology, Academic Medical Center/University of Amsterdam, Amsterdam, Netherlands
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Das UN. Arachidonic acid in health and disease with focus on hypertension and diabetes mellitus: A review. J Adv Res 2018; 11:43-55. [PMID: 30034875 PMCID: PMC6052660 DOI: 10.1016/j.jare.2018.01.002] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2017] [Revised: 01/01/2018] [Accepted: 01/02/2018] [Indexed: 02/06/2023] Open
Abstract
Arachidonic acid (AA 20:4n-6) is an essential component of cell membranes and modulates cell membrane fluidity. AA is metabolized by cyclo-oxygenase (COX), lipoxygenase (LOX) and cytochrome P450 enzymes to form several metabolites that have important biological actions. Of all the actions, role of AA in the regulation of blood pressure and its ability to prevent both type 1 and type 2 diabetes mellitus seems to be interesting. Studies showed that AA and its metabolites especially, lipoxin A4 (LXA4) and epoxyeicosatrienoic acids (EETs), potent anti-inflammatory metabolites, have a crucial role in the pathobiology of hypertension and diabetes mellitus. AA, LXA4 and EETs regulate smooth muscle function and proliferation, voltage gated ion channels, cell membrane fluidity, membrane receptors, G-coupled receptors, PPARs, free radical generation, nitric oxide formation, inflammation, and immune responses that, in turn, participate in the regulation blood pressure and pathogenesis of diabetes mellitus. In this review, role of AA and its metabolites LXA4 and EETs in the pathobiology of hypertension, pre-eclampsia and diabetes mellitus are discussed. Based on several lines of evidences, it is proposed that a combination of aspirin and AA could be of benefit in the prevention and management of hypertension, pre-eclampsia and diabetes mellitus.
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Samuels JS, Holland L, López M, Meyers K, Cumbie WG, McClain A, Ignatowicz A, Nelson D, Shashidharamurthy R. Prostaglandin E2 and IL-23 interconnects STAT3 and RoRγ pathways to initiate Th17 CD4 + T-cell development during rheumatoid arthritis. Inflamm Res 2018; 67:589-596. [PMID: 29713730 DOI: 10.1007/s00011-018-1153-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 04/16/2018] [Accepted: 04/23/2018] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND The chronic inflammation associated with rheumatoid arthritis (RA) leads to focal and systemic bone erosion of the joints resulting in a crippling disability. Recent reports indicate an increase in the incidence of RA in the coming years, placing a significant burden on healthcare resources. The incidence of RA is observed to be increasing with age and a significant proportion of those new cases will be aggressively erosive. FINDINGS The altered physiology, due to immune disturbances, contributes towards RA pathogenesis. The imbalance of inflammatory cytokines and non-cytokine immune modulators such as prostaglandin E2 (PGE2) and IL-23-induced pathogenic IL-17, plays a crucial role in persistent inflammation and bone degradation during RA. However, the molecular mechanism of IL-23, a key cytokine, and PGE2 in the development and perpetuation of IL-17 producing effector Th17 cells is poorly understood. CONCLUSION This review focuses on research findings that provide insight into the contribution of PGE2 and IL-23 during the development of pathogenic Th17 cells. We also highlight the key transcriptional factors required for Th17 development and therapeutic strategies to disrupt the interaction between IL-23 and IL-17 to prevent the end-organ damage in RA.
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Affiliation(s)
- Janaiya S Samuels
- Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine-Georgia Campus, Room 3031, 625 Old Peachtree Road, NW, Suwanee, GA, 30024, USA
| | - Lauren Holland
- Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine-Georgia Campus, Room 3031, 625 Old Peachtree Road, NW, Suwanee, GA, 30024, USA
| | - María López
- Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine-Georgia Campus, Room 3031, 625 Old Peachtree Road, NW, Suwanee, GA, 30024, USA
| | - Keya Meyers
- Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine-Georgia Campus, Room 3031, 625 Old Peachtree Road, NW, Suwanee, GA, 30024, USA
| | - William G Cumbie
- Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine-Georgia Campus, Room 3031, 625 Old Peachtree Road, NW, Suwanee, GA, 30024, USA
| | - Anna McClain
- Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine-Georgia Campus, Room 3031, 625 Old Peachtree Road, NW, Suwanee, GA, 30024, USA
| | - Aleksandra Ignatowicz
- Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine-Georgia Campus, Room 3031, 625 Old Peachtree Road, NW, Suwanee, GA, 30024, USA
| | - Daryllynn Nelson
- Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine-Georgia Campus, Room 3031, 625 Old Peachtree Road, NW, Suwanee, GA, 30024, USA
| | - Rangaiah Shashidharamurthy
- Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine-Georgia Campus, Room 3031, 625 Old Peachtree Road, NW, Suwanee, GA, 30024, USA.
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Orchard TS, Andridge RR, Yee LD, Lustberg MB. Diet Quality, Inflammation, and Quality of Life in Breast Cancer Survivors: A Cross-Sectional Analysis of Pilot Study Data. J Acad Nutr Diet 2018; 118:578-588.e1. [PMID: 29233615 PMCID: PMC5869134 DOI: 10.1016/j.jand.2017.09.024] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Accepted: 09/27/2017] [Indexed: 01/08/2023]
Abstract
BACKGROUND Modifiable lifestyle factors, such as diet quality, could reduce inflammation and improve quality of life (QOL) in breast cancer survivors, but data are inconclusive. OBJECTIVE To determine whether diet quality, as measured by Healthy Eating Index-2010 (HEI-2010) score, is associated with inflammation, health status, or functional outcomes affecting QOL in survivors of early-stage breast cancer. DESIGN This is a cross-sectional, secondary analysis of baseline data collected from breast cancer survivors after completion of primary therapy and before random assignment to a pilot nutritional intervention aimed at reducing side effects of aromatase inhibitor treatment. PARTICIPANTS/SETTING Participants were 44 postmenopausal women with stage I to III endocrine receptor-positive breast cancer receiving outpatient care at a midwestern cancer center between November 2011 and October 2013. MAIN OUTCOME MEASURES Primary outcomes were serum proinflammatory cytokines (interleukin-6 [IL-6], IL-17, and tumor necrosis factor-α receptor 2 [TNFR-2]). Secondary outcomes included QOL measured by the Stanford Health and Disability Questionnaire and the Functional Assessment of Cancer Therapy-Breast with Endocrine Subscale. STATISTICAL ANALYSES PERFORMED Pearson correlation coefficients (r) and linear regression models were used to evaluate the relationship of dietary variables with inflammatory cytokines and QOL measures. RESULTS A higher overall HEI-2010 score (healthier diet) was associated with lower IL-6 (r=-0.46; P=0.002) and TNFR-2 (r=-0.41; P=0.006); however, associations were attenuated by body mass index (BMI) (IL=6 [r=-0.26; P=0.10]; TNFR-2 [r=-0.30; P=0.06]). In women with prior chemotherapy, a higher HEI-2010 score was strongly associated with lower IL-6 (r=-0.67; P=0.009) and TNFR-2 (r=-0.59; P=0.03) after BMI adjustment. There were no significant correlations between HEI-2010 score and QOL measures after adjustment for BMI. CONCLUSIONS These data suggest the need for more rigorous investigation into the relationship of diet quality, BMI, and inflammation in breast cancer survivors.
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Caselli G, Bonazzi A, Lanza M, Ferrari F, Maggioni D, Ferioli C, Giambelli R, Comi E, Zerbi S, Perrella M, Letari O, Di Luccio E, Colovic M, Persiani S, Zanelli T, Mennuni L, Piepoli T, Rovati LC. Pharmacological characterisation of CR6086, a potent prostaglandin E 2 receptor 4 antagonist, as a new potential disease-modifying anti-rheumatic drug. Arthritis Res Ther 2018; 20:39. [PMID: 29490676 PMCID: PMC5831858 DOI: 10.1186/s13075-018-1537-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Accepted: 02/04/2018] [Indexed: 12/22/2022] Open
Abstract
Background Prostaglandin E2 (PGE2) acts via its EP4 receptor as a cytokine amplifier (e.g., interleukin [IL]-6) and induces the differentiation and expansion of inflammatory T-helper (Th) lymphocytes. These mechanisms play a key role in the onset and progression of rheumatoid arthritis (RA). We present the pharmacological characterisation of CR6086, a novel EP4 receptor antagonist, and provide evidence for its potential as a disease-modifying anti-rheumatic drug (DMARD). Methods CR6086 affinity and pharmacodynamics were studied in EP4-expressing HEK293 cells by radioligand binding and cyclic adenosine monophosphate (cAMP) production, respectively. In immune cells, IL-6 and vascular endothelial growth factor (VEGF) expression were analysed by RT-PCR, and IL-23 and IL-17 release were measured by enzyme-linked immunosorbent assay (ELISA). In collagen-induced arthritis (CIA) models, rats or mice were immunised with bovine collagen type II. Drugs were administered orally (etanercept and methotrexate intraperitoneally) starting at disease onset. Arthritis progression was evaluated by oedema, clinical score and histopathology. Anti-collagen II immunoglobulin G antibodies were measured by ELISA. Results CR6086 showed selectivity and high affinity for the human EP4 receptor (Ki = 16.6 nM) and functioned as a pure antagonist (half-maximal inhibitory concentration, 22 nM) on PGE2-stimulated cAMP production. In models of human immune cells in culture, CR6086 reduced key cytokine players of RA (IL-6 and VEGF expression in macrophages, IL-23 release from dendritic cells, IL-17 release from Th17 cells). In the CIA model of RA in rats and mice, CR6086 significantly improved all features of arthritis: severity, histology, inflammation and pain. In rats, CR6086 was better than the selective cyclooxygenase-2 inhibitor rofecoxib and at least as effective as the Janus kinase inhibitor tofacitinib. In mice, CR6086 and the biologic DMARD etanercept were highly effective, whereas the non-steroidal anti-inflammatory drug naproxen was ineffective. Importantly, in a study of CR6086/methotrexate, combined treatment greatly improved the effect of a fully immunosuppressive dose of methotrexate. Conclusions CR6086 is a novel, potent EP4 antagonist showing favourable immunomodulatory properties, striking DMARD effects in rodents, and anti-inflammatory activity targeted to immune-mediated inflammatory diseases and distinct from the general effects of cyclooxygenase inhibitors. These results support the clinical development of CR6086, both as a stand-alone DMARD and as a combination therapy with methotrexate. The proof-of-concept trial in patients with RA is ongoing. Electronic supplementary material The online version of this article (10.1186/s13075-018-1537-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
| | - Albino Bonazzi
- Rottapharm Biotech, Via Valosa di Sopra 9, I-20900, Monza, MB, Italy
| | - Marco Lanza
- Rottapharm Biotech, Via Valosa di Sopra 9, I-20900, Monza, MB, Italy
| | - Flora Ferrari
- Rottapharm Biotech, Via Valosa di Sopra 9, I-20900, Monza, MB, Italy
| | - Daniele Maggioni
- Rottapharm Biotech, Via Valosa di Sopra 9, I-20900, Monza, MB, Italy
| | - Cristian Ferioli
- Rottapharm Biotech, Via Valosa di Sopra 9, I-20900, Monza, MB, Italy
| | - Roberto Giambelli
- Rottapharm Biotech, Via Valosa di Sopra 9, I-20900, Monza, MB, Italy
| | - Eleonora Comi
- Rottapharm Biotech, Via Valosa di Sopra 9, I-20900, Monza, MB, Italy
| | - Silvia Zerbi
- Rottapharm Biotech, Via Valosa di Sopra 9, I-20900, Monza, MB, Italy
| | - Marco Perrella
- Rottapharm Biotech, Via Valosa di Sopra 9, I-20900, Monza, MB, Italy
| | - Ornella Letari
- Rottapharm Biotech, Via Valosa di Sopra 9, I-20900, Monza, MB, Italy
| | - Elena Di Luccio
- Rottapharm Biotech, Via Valosa di Sopra 9, I-20900, Monza, MB, Italy
| | - Milena Colovic
- Rottapharm Biotech, Via Valosa di Sopra 9, I-20900, Monza, MB, Italy
| | - Stefano Persiani
- Rottapharm Biotech, Via Valosa di Sopra 9, I-20900, Monza, MB, Italy
| | - Tiziano Zanelli
- Rottapharm Biotech, Via Valosa di Sopra 9, I-20900, Monza, MB, Italy
| | - Laura Mennuni
- Rottapharm Biotech, Via Valosa di Sopra 9, I-20900, Monza, MB, Italy
| | - Tiziana Piepoli
- Rottapharm Biotech, Via Valosa di Sopra 9, I-20900, Monza, MB, Italy
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Molecular mechanisms underpinning T helper 17 cell heterogeneity and functions in rheumatoid arthritis. J Autoimmun 2018; 87:69-81. [DOI: 10.1016/j.jaut.2017.12.006] [Citation(s) in RCA: 90] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 12/05/2017] [Indexed: 12/24/2022]
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Maseda D, Johnson EM, Nyhoff LE, Baron B, Kojima F, Wilhelm AJ, Ward MR, Woodward JG, Brand DD, Crofford LJ. mPGES1-Dependent Prostaglandin E 2 (PGE 2) Controls Antigen-Specific Th17 and Th1 Responses by Regulating T Autocrine and Paracrine PGE 2 Production. THE JOURNAL OF IMMUNOLOGY 2017; 200:725-736. [PMID: 29237778 DOI: 10.4049/jimmunol.1601808] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Accepted: 11/06/2017] [Indexed: 01/24/2023]
Abstract
The integration of inflammatory signals is paramount in controlling the intensity and duration of immune responses. Eicosanoids, particularly PGE2, are critical molecules in the initiation and resolution of inflammation and in the transition from innate to acquired immune responses. Microsomal PGE synthase 1 (mPGES1) is an integral membrane enzyme whose regulated expression controls PGE2 levels and is highly expressed at sites of inflammation. PGE2 is also associated with modulation of autoimmunity through altering the IL-23/IL-17 axis and regulatory T cell (Treg) development. During a type II collagen-CFA immunization response, lack of mPGES1 impaired the numbers of CD4+ regulatory (Treg) and Th17 cells in the draining lymph nodes. Ag-experienced mPGES1-/- CD4+ cells showed impaired IL-17A, IFN-γ, and IL-6 production when rechallenged ex vivo with their cognate Ag compared with their wild-type counterparts. Additionally, production of PGE2 by cocultured APCs synergized with that of Ag-experienced CD4+ T cells, with mPGES1 competence in the APC compartment enhancing CD4+ IL-17A and IFN-γ responses. However, in contrast with CD4+ cells that were Ag primed in vivo, exogenous PGE2 inhibited proliferation and skewed IL-17A to IFN-γ production under Th17 polarization of naive T cells in vitro. We conclude that mPGES1 is necessary in vivo to mount optimal Treg and Th17 responses during an Ag-driven primary immune response. Furthermore, we uncover a coordination of autocrine and paracrine mPGES1-driven PGE2 production that impacts effector T cell IL-17A and IFN-γ responses.
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Affiliation(s)
- Damian Maseda
- Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37202
| | - Elizabeth M Johnson
- Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37202
| | - Lindsay E Nyhoff
- Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37202
| | - Bridgette Baron
- Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37202
| | - Fumiaki Kojima
- Department of Pharmacology, Kitasato University, Tokyo 108-8641, Japan
| | - Ashley J Wilhelm
- Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37202
| | - Martin R Ward
- University of Kentucky Medical Center, Lexington, KY 40536; and
| | | | - David D Brand
- Division of Rheumatology, University of Tennessee, Memphis, TN 38104
| | - Leslie J Crofford
- Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37202;
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Lipopolysaccharide (LPS)-mediated priming of toll-like receptor 4 enhances oxidant-induced prostaglandin E 2 biosynthesis in primary murine macrophages. Int Immunopharmacol 2017; 54:226-237. [PMID: 29161659 DOI: 10.1016/j.intimp.2017.11.017] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Revised: 11/13/2017] [Accepted: 11/14/2017] [Indexed: 12/17/2022]
Abstract
Agonists and pseudo-agonists for toll-like receptor 4 (TLR4) are common in our environment. Thus, human exposure to these agents may result in "priming or sensitization" of TLR4. A body of evidence suggests that LPS-mediated sensitization of TLR4 can increase the magnitude of responses to exogenous agents in multiple tissues. We have previously shown that reactive oxygen and nitrogen species (RONS) stimulate TLR4. There is no evidence that LPS-primed TLR4 can influence the magnitude of responses to oxidants from either endogenous or exogenous sources. In the present study, we directly tested the hypothesis that LPS-primed TLR4 will sensitize primary murine peritoneal macrophages (pM) to oxidant-mediated prostaglandin E2 (PGE2) production. We used potassium peroxychromate (PPC) and potassium peroxynitrite (PPN) as direct in vitro sources of exogenous RONS. Our results showed that a direct treatment with PPC or PPN alone as sources of exogenous oxidants had a limited effect on PGE2 biosynthesis. In contrast, pM sensitized by prior incubation with LPS-EK, a TLR4-specific agonist, followed by oxidant stimulation exhibited increased transcriptional and translational expression of cyclooxygenase-2 (COX-2) with enhanced PGE2 biosynthesis/production only in pM derived from TLR4-WT mice but not in TLR4-KO mice. Thus, we have shown a critical role for LPS-primed TLR4 in oxidant-induced inflammatory phenotypes that have the potential to initiate, propagate and maintain many human diseases.
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Abstract
Bioactive lipids regulate most physiological processes, from digestion to blood flow and from hemostasis to labor. Lipid mediators are also involved in multiple pathologies including cancer, autoimmunity or asthma. The pathological roles of lipid mediators are based on their intricate involvement in the immune system, which comprises source and target cells of these mediators. Based on their biosynthetic origin, bioactive lipids can be grouped into different classes [e.g. sphingolipids, formed from sphingosine or eicosanoids, formed from arachidonic acid (AA)]. Owing to the complexity of different mediator classes and the prominent immunological roles of eicosanoids, this review will focus solely on the immune-regulation of eicosanoids. Eicosanoids do not only control key immune responses (e.g. chemotaxis, antigen presentation, phagocytosis), but they are also subject to reciprocal control by the immune system. Particularly, key immunoregulatory cytokines such as IL-4 and IFN-γ shape the cellular eicosanoid profile, thus providing efficient feedback regulation between cytokine and eicosanoid networks. For the purpose of this review, I will first provide a short overview of the most important immunological functions of eicosanoids with a focus on prostaglandins (PGs) and leukotrienes (LTs). Second, I will summarize the current knowledge on immunological factors that regulate eicosanoid production during infection and inflammation.
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Liu Y, Li L, Liu J, She WM, Shi JM, Li J, Wang JY, Jiang W. Activated hepatic stellate cells directly induce pathogenic Th17 cells in chronic hepatitis B virus infection. Exp Cell Res 2017; 359:129-137. [PMID: 28780305 DOI: 10.1016/j.yexcr.2017.08.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2017] [Revised: 08/01/2017] [Accepted: 08/02/2017] [Indexed: 02/08/2023]
Abstract
Th17 cells are involved in liver fibrosis by activating hepatic stellate cells (HSCs). We aimed to investigate whether HSCs are able to regulate the function of Th17 cells and to determine the relevant mechanism. Sixty-five patients diagnosed with chronic hepatitis B (CHB) were enrolled in this study. To determine the effect of HSCs on T cells, naïve CD4+T cells and Th17 cells were sorted from CHB patients and cultured with or without activated-HSCs, and cytokine expression and gene transcription were analyzed. In addition, the regulatory mechanism of HSCs was investigated. ELISA and qRT-PCR showed that Th17 cells from CHB patients were more pathogenic, on the basis of the expression of IL-17A, IL-23R, RORC, CCL20 and CCR6, and meanwhile, they could activate the primary HSCs. Co-culture experiments indicated that activated HSCs dramatically promoted proliferation of CD4+T cells in a time- and dose-dependent manner. In addition, they could induce naïve CD4+T cells to become Th17 cells which had a more pathogenic phenotype. Moreover, activated HSCs-mediated induction of Th17 cells might depend on the release of IL-1β and IL-6 as well as on the COX-PGE2 pathway. Th17 cells cooperated with HSCs in a proinflammatory feedback loop might provide a better understanding of the pathogenic role of Th17 cells in the chronicity of HBV infection.
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Affiliation(s)
- Yun Liu
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Lei Li
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Jiang Liu
- Department of Gastroenterology, Huzhou Central Hospital, Zhejiang 313003, China
| | - Wei-Min She
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Jie-Min Shi
- Department of Gastroenterology, Huzhou Central Hospital, Zhejiang 313003, China
| | - Jing Li
- Department of Gastroenterology, Tongji Hospital, Tongji University, Shanghai 200065, China
| | - Ji-Yao Wang
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Wei Jiang
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
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Hooper KM, Kong W, Ganea D. Prostaglandin E2 inhibits Tr1 cell differentiation through suppression of c-Maf. PLoS One 2017; 12:e0179184. [PMID: 28604806 PMCID: PMC5467903 DOI: 10.1371/journal.pone.0179184] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Accepted: 05/07/2017] [Indexed: 12/30/2022] Open
Abstract
Prostaglandin E2 (PGE2), a major lipid mediator abundant at inflammatory sites, acts as a proinflammatory agent in models of inflammatory/autoimmune diseases by promoting CD4 Th1/Th17 differentiation. Regulatory T cells, including the IL-10 producing Tr1 cells counterbalance the proinflammatory activity of effector Th1/Th17 cells. Tr1 cell differentiation and function are induced by IL-27, and depend primarily on sustained expression of c-Maf in addition to AhR and Blimp-1. In agreement with the in vivo proinflammatory role of PGE2, here we report for the first time that PGE2 inhibits IL-27-induced differentiation and IL-10 production of murine CD4+CD49b+LAG-3+Foxp3- Tr1 cells. The inhibitory effect of PGE2 was mediated through EP4 receptors and induction of cAMP, leading to a significant reduction in c-Maf expression. Although PGE2 reduced IL-21 production in differentiating Tr1 cells, its inhibitory effect on Tr1 differentiation and c-Maf expression also occurred independent of IL-21 signaling. PGE2 did not affect STAT1/3 activation, AhR expression and only marginally reduced Egr-2/Blimp-1 expression. The effect of PGE2 on CD4+CD49b+LAG-3+ Tr1 differentiation was not associated with either induction of Foxp3 or IL-17 production, suggesting a lack of transdifferentiation into Foxp3+ Treg or effector Th17 cells. We recently reported that PGE2 inhibits the expression and production of IL-27 from activated conventional dendritic cells (cDC) in vivo and in vitro. The present study indicates that PGE2 also reduces murine Tr1 differentiation and function directly by acting on IL-27-differentiating Tr1 cells. Together, the ability of PGE2 to inhibit IL-27 production by cDC, and the direct inhibitory effect on Tr1 differentiation mediated through reduction in c-Maf expression, represent a new mechanistic perspective for the proinflammatory activity of PGE2.
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Affiliation(s)
- Kirsten Mary Hooper
- Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, United States of America
| | - Weimin Kong
- Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, United States of America
| | - Doina Ganea
- Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, United States of America
- * E-mail:
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Hooper KM, Yen JH, Kong W, Rahbari KM, Kuo PC, Gamero AM, Ganea D. Prostaglandin E2 Inhibition of IL-27 Production in Murine Dendritic Cells: A Novel Mechanism That Involves IRF1. THE JOURNAL OF IMMUNOLOGY 2017; 198:1521-1530. [PMID: 28062696 DOI: 10.4049/jimmunol.1601073] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 12/09/2016] [Indexed: 12/20/2022]
Abstract
IL-27, a multifunctional cytokine produced by APCs, antagonizes inflammation by affecting conventional dendritic cells (cDC), inducing IL-10, and promoting development of regulatory Tr1 cells. Although the mechanisms involved in IL-27 induction are well studied, much less is known about the factors that negatively impact IL-27 expression. PGE2, a major immunomodulatory prostanoid, acts as a proinflammatory agent in several models of inflammatory/autoimmune disease, promoting primarily Th17 development and function. In this study, we report on a novel mechanism that promotes the proinflammatory function of PGE2 We showed previously that PGE2 inhibits IL-27 production in murine bone marrow-derived DCs. In this study, we show that, in addition to bone marrow-derived DCs, PGE2 inhibits IL-27 production in macrophages and in splenic cDC, and we identify a novel pathway consisting of signaling through EP2/EP4→induction of cAMP→downregulation of IFN regulatory factor 1 expression and binding to the p28 IFN-stimulated response element site. The inhibitory effect of PGE2 on p28 and irf1 expression does not involve endogenous IFN-β, STAT1, or STAT2, and inhibition of IL-27 does not appear to be mediated through PKA, exchange protein activated by cAMP, PI3K, or MAPKs. We observed similar inhibition of il27p28 expression in vivo in splenic DC following administration of dimethyl PGE2 in conjunction with LPS. Based on the anti-inflammatory role of IL-27 in cDC and through the generation of Tr1 cells, we propose that the PGE2-induced inhibition of IL-27 in activated cDC represents an important additional mechanism for its in vivo proinflammatory functions.
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Affiliation(s)
- Kirsten M Hooper
- Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140
| | - Jui-Hung Yen
- Department of Microbiology and Immunology, Indiana University School of Medicine, Fort Wayne, IN 46202
| | - Weimin Kong
- Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140
| | - Kate M Rahbari
- Department of Microbiology and Immunology, University of Illinois College of Medicine at Chicago, Chicago, IL 60612; and
| | - Ping-Chang Kuo
- Department of Microbiology and Immunology, Indiana University School of Medicine, Fort Wayne, IN 46202
| | - Ana M Gamero
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140
| | - Doina Ganea
- Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140;
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Akasaka H, Thaliachery N, Zheng X, Blumenthal M, Nikhar S, Murdoch EE, Ling Q, Ruan KH. The key residue within the second extracellular loop of human EP3 involved in selectively turning down PGE 2- and retaining PGE 1-mediated signaling in live cells. Arch Biochem Biophys 2017; 616:20-29. [PMID: 28065721 DOI: 10.1016/j.abb.2016.12.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Revised: 11/15/2016] [Accepted: 12/02/2016] [Indexed: 10/20/2022]
Abstract
Key residues and binding mechanisms of PGE1 and PGE2 on prostanoid receptors are poorly understood due to the lack of X-ray structures for the receptors. We constructed a human EP3 (hEP3) model through integrative homology modeling using the X-ray structure of the β2-adrenergic receptor transmembrane domain and NMR structures of the thromboxane A2 receptor extracellular loops. PGE1 and PGE2 docking into the hEP3 model showed differing configurations within the extracellular ligand recognition site. While PGE2 could form possible binding contact with S211, PGE1 is unable to form similar contacts. Therefore, S211 could be the critical residue for PGE2 recognition, but is not a significant for PGE1. This prediction was confirmed using HEK293 cells transfected with hEP3 S211L cDNA. The S211L cells lost PGE2 binding and signaling. Interestingly, the S211L cells retained PGE1-mediated signaling. It indicates that S211 within the second extracellular loop is a key residue involved in turning down PGE2 signaling. Our study provided information that S211L within EP3 is the key residue to distinguish PGE1 and PGE2 binding to mediate diverse biological functions at the initial recognition step. The S211L mutant could be used as a model for studying the binding mechanism and signaling pathway specifically mediated by PGE1.
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Affiliation(s)
- Hironari Akasaka
- Center for Experimental Therapeutics and Pharmacoinformatics and Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX 77204-5037, USA
| | - Natasha Thaliachery
- Center for Experimental Therapeutics and Pharmacoinformatics and Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX 77204-5037, USA
| | - Xianghai Zheng
- Center for Experimental Therapeutics and Pharmacoinformatics and Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX 77204-5037, USA
| | - Marissa Blumenthal
- Center for Experimental Therapeutics and Pharmacoinformatics and Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX 77204-5037, USA
| | - Sameer Nikhar
- Center for Experimental Therapeutics and Pharmacoinformatics and Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX 77204-5037, USA
| | - Emma E Murdoch
- Center for Experimental Therapeutics and Pharmacoinformatics and Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX 77204-5037, USA
| | - Qinglan Ling
- Center for Experimental Therapeutics and Pharmacoinformatics and Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX 77204-5037, USA
| | - Ke-He Ruan
- Center for Experimental Therapeutics and Pharmacoinformatics and Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX 77204-5037, USA
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Rozenberg A, Rezk A, Boivin MN, Darlington PJ, Nyirenda M, Li R, Jalili F, Winer R, Artsy EA, Uccelli A, Reese JS, Planchon SM, Cohen JA, Bar-Or A. Human Mesenchymal Stem Cells Impact Th17 and Th1 Responses Through a Prostaglandin E2 and Myeloid-Dependent Mechanism. Stem Cells Transl Med 2016; 5:1506-1514. [PMID: 27400792 PMCID: PMC5070498 DOI: 10.5966/sctm.2015-0243] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Accepted: 05/02/2016] [Indexed: 12/13/2022] Open
Abstract
: Human mesenchymal stem cells (hMSCs) are being increasingly pursued as potential therapies for immune-mediated conditions, including multiple sclerosis. Although they can suppress human Th1 responses, they reportedly can reciprocally enhance human Th17 responses. Here, we investigated the mechanisms underlying the capacity of hMSCs to modulate human Th1 and Th17 responses. Human adult bone marrow-derived MSCs were isolated, and their purity and differentiation capacity were confirmed. Human venous peripheral blood mononuclear cells (PBMC) were activated, alone, together with hMSC, or in the presence of hMSC-derived supernatants (sups). Cytokine expression by CD4+ T-cell subsets (intracellular staining by fluorescence-activated cell sorting) and secreted cytokines (enzyme-linked immunosorbent assay) were then quantified. The contribution of prostaglandin E2 (PGE2) as well as of myeloid cells to the hMSC-mediated regulation of T-cell responses was investigated by selective depletion of PGE2 from the hMSC sups (anti-PGE2 beads) and by the selective removal of CD14+ cells from the PBMC (magnetic-activated cell sorting separation). Human MSC-secreted products could reciprocally induce interleukin-17 expression while decreasing interferon-γ expression by human CD4+ T cells, both in coculture and through soluble products. Pre-exposure of hMSCs to IL-1β accentuated their capacity to reciprocally regulate Th1 and Th17 responses. Human MSCs secreted high levels of PGE2, which correlated with their capacity to regulate the T-cell responses. Selective removal of PGE2 from the hMSC supernatants abrogated the impact of hMSC on the T cells. Selective removal of CD14+ cells from the PBMCs also limited the capacity of hMSC-secreted PGE2 to affect T-cell responses. Our discovery of a novel PGE2-dependent and myeloid cell-mediated mechanism by which human MSCs can reciprocally induce human Th17 while suppressing Th1 responses has implications for the use of, as well as monitoring of, MSCs as a potential therapeutic for patients with multiple sclerosis and other immune-mediated diseases. SIGNIFICANCE Although animal studies have generated a growing interest in the anti-inflammatory potential of mesenchymal stem cells (MSCs) for the treatment of autoimmune diseases, MSCs possess the capacity to both limit and promote immune responses. Yet relatively little is known about human-MSC modulation of human disease-implicated T-cell responses, or the mechanisms underlying such modulation. The current study reveals a novel prostaglandin E2-dependent and myeloid cell-mediated mechanism by which human MSCs can reciprocally regulate human Th17 and Th1 responses, with implications for the use of MSCs as a potential therapeutic for patients with multiple sclerosis and other immune-mediated diseases.
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Affiliation(s)
- Ayal Rozenberg
- Neuroimmunology Unit, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
- Neuroimmunology Unit, Rambam Medical Center, Haifa, Israel
| | - Ayman Rezk
- Neuroimmunology Unit, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
| | - Marie-Noëlle Boivin
- Neuroimmunology Unit, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
| | - Peter J Darlington
- Department of Exercise Science, Concordia University, Montreal, Quebec, Canada
| | - Mukanthu Nyirenda
- Neuroimmunology Unit, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
| | - Rui Li
- Neuroimmunology Unit, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
| | - Farzaneh Jalili
- Neuroimmunology Unit, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
| | - Raz Winer
- Neuroimmunology Unit, Rambam Medical Center, Haifa, Israel
| | - Elinor A Artsy
- American Medical Students Program, Technion Institute of Technology, Haifa, Israel
| | - Antonio Uccelli
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health, University of Genoa, Genova, Italy
- Center of Excellence for Biomedical Research, University of Genoa, Genova, Italy
| | - Jane S Reese
- National Center for Regenerative Medicine, Case Western Reserve University, and University Hospitals Seidman Cancer Center, Cleveland, Ohio, USA
| | - Sarah M Planchon
- Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Jeffrey A Cohen
- Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Amit Bar-Or
- Neuroimmunology Unit, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
- Experimental Therapeutics Program, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
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Ren S, Hu J, Chen Y, Yuan T, Hu H, Li S. Human umbilical cord derived mesenchymal stem cells promote interleukin-17 production from human peripheral blood mononuclear cells of healthy donors and systemic lupus erythematosus patients. Clin Exp Immunol 2015; 183:389-96. [PMID: 26507122 DOI: 10.1111/cei.12737] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/22/2015] [Indexed: 01/14/2023] Open
Abstract
Inflammation instigated by interleukin (IL)-17-producing cells is central to the development and pathogenesis of several human autoimmune diseases and animal models of autoimmunity. The expansion of IL-17-producing cells from healthy donors is reportedly promoted by mesenchymal stem cells derived from fetal bone marrow. In the present study, human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) were examined for their effects on lymphocytes from healthy donors and from patients with systemic lupus erythematosus (SLE). Significantly higher levels of IL-17 were produced when CD4(+) T cells from healthy donors were co-cultured with hUC-MSCs than those that were cultured alone. Blocking experiments identified that this effect might be mediated partially through prostaglandin E2 (PGE2 ) and IL-1β, without IL-23 involvement. We then co-cultured hUC-MSCs with human CD4(+) T cells from systemic lupus erythematosus patients. Ex-vivo inductions of IL-17 by hUC-MSCs in stimulated lymphocytes were significantly higher in SLE patients than in healthy donors. This effect was not observed for IL-23. Taken together, our results represent that hUC-MSCs can promote the IL-17 production from CD4(+) T cells in both healthy donor and SLE patients. PGE2 and IL-1β might also be partially involved in the promotive effect of hUC-MSCs.
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Affiliation(s)
- S Ren
- Department of Hematology, National Center for Clinical Laboratories and Beijing Hospital, Beijing, China
| | - J Hu
- Department of Hematology, National Center for Clinical Laboratories and Beijing Hospital, Beijing, China
| | - Y Chen
- Department of Hepatobiliary Surgery, General Hospital of Beijing Military Area Command, Beijing, China
| | - T Yuan
- Department of Hematology, National Center for Clinical Laboratories and Beijing Hospital, Beijing, China
| | - H Hu
- Department of Hematology, National Center for Clinical Laboratories and Beijing Hospital, Beijing, China
| | - S Li
- Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics, Ministry of Education, Key Laboratory of Major Diseases in Children, Ministry of Education, Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, Beijing, China
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Abadir PM, Siragy HM. Angiotensin type 1 receptor mediates renal production and conversion of prostaglandins E2 to F2α in conscious diabetic rats. J Renin Angiotensin Aldosterone Syst 2015. [PMID: 26195268 DOI: 10.1177/1470320315592566] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
INTRODUCTION Previous studies demonstrated that stimulation of angiotensin subtype 1 receptor (AT1R) led to increased renal generation of prostaglandins E2 (PGE2) and renal inflammation. In turn, PGE2 increases AT1R activity. The conversion of PGE2 to the less active metabolite prostaglandin F2α (PGF2α) via 9-ketoreductase interrupts this feedback loop. The effects of diabetes on the interface between AT1R, PGE2 and PGF2α are not well established. We hypothesized that in diabetes, an aberrant AT1R activity enhances the biosynthesis of PGE2 and impairs the activity of PGE 9-ketoreductase, leading to accumulation of PGE2. MATERIALS AND METHODS Using microdialysis technique, we monitored renal interstitial fluid levels of angiotensin II (Ang II), PGE2 and PGF2α in control and AT1R blocker, valsartan, treated diabetic rats (N=8 each). We utilized the PGF2α to PGE2 ratio as indirect measure of PGE 9-ketoreductase activity. RESULTS Diabetes increased renal interstitial fluid levels of Ang II, PGE2 and PGF2α. PGF2α/PGE2 ratio increased by the third week, but declined by the sixth week of diabetes. Valsartan reduced PGE2 and PGF2α levels and increased Ang II and the conversion of PGE2 to PGF2α. CONCLUSION Our results suggest that in diabetes, AT1R increases PGE2 generation and reduces conversion of PGE2 to PGF2α with the progression of diabetes.
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Affiliation(s)
- Peter M Abadir
- Johns Hopkins University, Division of Geriatrics Medicine and Gerontology, Baltimore, USA
| | - Helmy M Siragy
- University of Virginia School of Medicine, Department of Medicine, Charlottesville, USA
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Uccelli A, de Rosbo NK. The immunomodulatory function of mesenchymal stem cells: mode of action and pathways. Ann N Y Acad Sci 2015; 1351:114-26. [PMID: 26152292 DOI: 10.1111/nyas.12815] [Citation(s) in RCA: 149] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Revised: 05/13/2015] [Accepted: 05/18/2015] [Indexed: 12/21/2022]
Abstract
Mesenchymal stem cells (MSCs) are being increasingly investigated as a therapeutic alternative, not only for their possible regenerative potential but also for their immunomodulatory action, which is being exploited for controlling diseases associated with inflammation. Understanding their direct and indirect target cells, as well as their mode of action and relevant pathways, is a prerequisite for the appropriate and optimal use of MSCs in therapy. Here, we review recent findings on the effects of MSCs on adaptive and innate immune cells. We also consider the impact of the environment on MSC profile, both anti- and proinflammatory, and the mechanisms and molecular pathways through which their effects are mediated, both at the MSC and target cell levels.
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Affiliation(s)
- Antonio Uccelli
- Department of Neurology, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (DINOGMI).,Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy
| | - Nicole Kerlero de Rosbo
- Department of Neurology, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (DINOGMI)
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El-Rifaie AA, Rashed LA, Doss RW. The role of cyclooxygenase-2 and prostaglandin E2 in the pathogenesis of cutaneous lichen planus. Clin Exp Dermatol 2015; 40:903-7. [DOI: 10.1111/ced.12663] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/19/2014] [Indexed: 01/27/2023]
Affiliation(s)
- A. A. El-Rifaie
- Dermatology Department; Faculty of Medicine; Beni Suef University; Beni Suef Egypt
| | - L. A. Rashed
- Biochemistry Department; Faculty of Medicine; Cairo University; Cairo Egypt
| | - R. W. Doss
- Dermatology Department; Faculty of Medicine; Beni Suef University; Beni Suef Egypt
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Abdollahi E, Tavasolian F, Ghasemi N, Mirghanizadeh SA, Azizi M, Ghoryani M, Samadi M. Association between lower frequency of R381Q variant (rs11209026) in IL-23 receptor gene and increased risk of recurrent spontaneous abortion (RSA). J Immunotoxicol 2014; 12:317-21. [DOI: 10.3109/1547691x.2014.978056] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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