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Nguyen TNB, Ely BA, Pick D, Patel M, Xie H, Kim-Schulze S, Gabbay V. Clenbuterol attenuates immune reaction to lipopolysaccharide and its relationship to anhedonia in adolescents. Brain Behav Immun 2022; 106:89-99. [PMID: 35914697 PMCID: PMC9817216 DOI: 10.1016/j.bbi.2022.07.163] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 07/25/2022] [Accepted: 07/27/2022] [Indexed: 02/01/2023] Open
Abstract
While inflammation has been implicated in psychopathology, relationships between immune-suppressing processes and psychiatric constructs remain elusive. This study sought to assess whether β2-agonist clenbuterol (CBL) would attenuate immune activation in adolescents with mood and anxiety symptoms following ex vivo exposure of whole blood to lipopolysaccharide (LPS). Our focus on adolescents aimed to target a critical developmental period when psychiatric conditions often emerge and prior to chronicity effects. To capture a diverse range of immunologic and symptomatologic phenotypes, we included 97 psychotropic-medication free adolescents with mood and anxiety symptoms and 33 healthy controls. All participants had comprehensive evaluations and dimensional assessments of psychiatric symptoms. Fasting whole-blood samples were collected and stimulated with LPS in the presence and absence of CBL for 6 hours, then analyzed for 41 cytokines, chemokines, and hematopoietic growth factors. Comparison analyses used Bonferroni-corrected nonparametric tests. Levels of nine immune biomarkers-including IL-1RA, IL-1β, IL-6, IP-10, MCP-1, MIP-1α, MIP-1β, TGF-α, and TNF-α-were significantly reduced by CBL treatment compared to LPS alone. Exploratory factor analysis reduced 41 analytes into 5 immune factors in each experimental condition, and their relationships with psychiatric symptoms were examined as a secondary aim. CBL + LPS Factor 4-comprising EGF, PDGF-AA, PDGF-AB/BB, sCD40L, and GRO-significantly correlated with anticipatory and consummatory anhedonia, even after controlling for depression severity. This study supports the possible inhibitory effect of CBL on immune activation. Using a data-driven method, distinctive relationships between CBL-affected immune biomarkers and dimensional anhedonia were reported, further elucidating the role of β2-agonism in adolescent affective symptomatology.
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Affiliation(s)
- Tram N B Nguyen
- Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY, United States.
| | - Benjamin A Ely
- Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY, United States.
| | - Danielle Pick
- Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY, United States.
| | - Manishkumar Patel
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
| | - Hui Xie
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
| | - Seunghee Kim-Schulze
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
| | - Vilma Gabbay
- Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY, United States; Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, United States.
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2
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Gu Y, Li L, Yang M, Liu T, Song X, Qin X, Xu X, Liu J, Wang B, Cao H. Bile acid-gut microbiota crosstalk in irritable bowel syndrome. Crit Rev Microbiol 2022; 49:350-369. [PMID: 35389754 DOI: 10.1080/1040841x.2022.2058353] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Irritable bowel syndrome (IBS) is a common disorder of gut-brain interaction with an increasing prevalence, and its precise aetiology remains unclear. Gut microbiota dysbiosis has been found to be associated with IBS pathogenesis. In addition, a high incidence of bile acid diarrhoea and disturbed bile acid metabolism has been observed in IBS patients. The abundant microorganisms inhabited in human gut have essential functions in bile acid biotransformation, and can immensely affect the size and constitution of bile acid pool. Meanwhile, the alterations of bile acid profile can inversely interfere with the gut microbiota. This review discussed the role of intricate correlations between bile acids and gut microbiota in IBS pathogenesis and delineated the possible molecular mechanisms, mainly the signalling induced by farnesoid X receptor and transmembrane G protein-coupled receptor 5. Besides, some biomarkers for identifying bile acid diarrhoea in IBS population were listed, assisting the diagnosis and classification of IBS. Moreover, it also assessed some therapeutic strategies for IBS that regulate the bile acid-gut microbiota axis, such as dietary modulation, probiotics/prebiotics, faecal microbiota transplantation, and antibiotics. Collectively, this article illustrated the relationship between bile acids and gut microbiota in IBS pathophysiology and might offer some novel therapeutic options for IBS.
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Affiliation(s)
- Yu Gu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Lingfeng Li
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Min Yang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Tianyu Liu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Xueli Song
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Xiali Qin
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Xin Xu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Jinghua Liu
- Department of Gastroenterology, Tianjin TEDA hospital, Tianjin, China
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Hailong Cao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
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3
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Witkowska-Piłaszewicz O, Pingwara R, Szczepaniak J, Winnicka A. The Effect of the Clenbuterol-β2-Adrenergic Receptor Agonist on the Peripheral Blood Mononuclear Cells Proliferation, Phenotype, Functions, and Reactive Oxygen Species Production in Race Horses In Vitro. Cells 2021; 10:cells10040936. [PMID: 33920705 PMCID: PMC8072563 DOI: 10.3390/cells10040936] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 04/14/2021] [Accepted: 04/15/2021] [Indexed: 12/21/2022] Open
Abstract
Clenbuterol, the β2-adrenoceptor agonist, is gaining growing popularity because of its effects on weight loss (i.e., chemical liposuction). It is also popular in bodybuilding and professional sports, due to its effects that are similar to anabolic steroids. However, it is prohibited by anti-doping control. On the other hand, it is suggested that clenbuterol can inhibit the inflammatory process. The cells from 14 untrained and 14 well-trained race horses were collected after acute exercise and cultured with clenbuterol. The expressions of CD4, CD8, FoxP3, CD14, MHCII, and CD5 in PBMC, and reactive oxygen species (ROS) production, as well as cell proliferation, were evaluated by flow cytometry. In addition, IL-1β, IL-4, IL-6, IL-10, IL-17, INF-γ and TNF-α concentrations were evaluated by ELISA. β2-adrenoceptor stimulation leads to enhanced anti-inflammatory properties in well-trained horses, as do low doses in untrained animals. In contrast, higher clenbuterol doses create a pro-inflammatory environment in inexperienced horses. In conclusion, β2-adrenoceptor stimulation leads to a biphasic response. In addition, the immune cells are more sensitive to drug abuse in inexperienced individuals under physical training.
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Affiliation(s)
- Olga Witkowska-Piłaszewicz
- Department of Pathology and Veterinary Diagnostics, Institute of Veterinary Medicine, Warsaw University of Life Science—SGGW, 02-787 Warsaw, Poland;
- Correspondence:
| | - Rafał Pingwara
- Department of Physiological Sciences, Institute of Veterinary Medicine, Warsaw University of Life Sciences—SGGW, 02-787 Warsaw, Poland;
| | - Jarosław Szczepaniak
- Department of Nanobiotechnology, Institute of Biology, Warsaw University of Life Sciences—SGGW, 02-787 Warsaw, Poland;
| | - Anna Winnicka
- Department of Pathology and Veterinary Diagnostics, Institute of Veterinary Medicine, Warsaw University of Life Science—SGGW, 02-787 Warsaw, Poland;
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4
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Yi B, Jahangir A, Evans AK, Briggs D, Ravina K, Ernest J, Farimani AB, Sun W, Rajadas J, Green M, Feinberg EN, Pande VS, Shamloo M. Discovery of novel brain permeable and G protein-biased beta-1 adrenergic receptor partial agonists for the treatment of neurocognitive disorders. PLoS One 2017; 12:e0180319. [PMID: 28746336 PMCID: PMC5529018 DOI: 10.1371/journal.pone.0180319] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Accepted: 06/14/2017] [Indexed: 01/09/2023] Open
Abstract
The beta-1 adrenergic receptor (ADRB1) is a promising therapeutic target intrinsically involved in the cognitive deficits and pathological features associated with Alzheimer's disease (AD). Evidence indicates that ADRB1 plays an important role in regulating neuroinflammatory processes, and activation of ADRB1 may produce neuroprotective effects in neuroinflammatory diseases. Novel small molecule modulators of ADRB1, engineered to be highly brain permeable and functionally selective for the G protein with partial agonistic activity, could have tremendous value both as pharmacological tools and potential lead molecules for further preclinical development. The present study describes our ongoing efforts toward the discovery of functionally selective partial agonists of ADRB1 that have potential therapeutic value for AD and neuroinflammatory disorders, which has led to the identification of the molecule STD-101-D1. As a functionally selective agonist of ADRB1, STD-101-D1 produces partial agonistic activity on G protein signaling with an EC50 value in the low nanomolar range, but engages very little beta-arrestin recruitment compared to the unbiased agonist isoproterenol. STD-101-D1 also inhibits the tumor necrosis factor α (TNFα) response induced by lipopolysaccharide (LPS) both in vitro and in vivo, and shows high brain penetration. Other than the therapeutic role, this newly identified, functionally selective, partial agonist of ADRB1 is an invaluable research tool to study mechanisms of G protein-coupled receptor signal transduction.
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MESH Headings
- Adrenergic beta-1 Receptor Agonists/chemistry
- Adrenergic beta-1 Receptor Agonists/pharmacokinetics
- Adrenergic beta-1 Receptor Agonists/therapeutic use
- Alzheimer Disease/drug therapy
- Alzheimer Disease/metabolism
- Animals
- Brain/metabolism
- CHO Cells
- Cell Line, Tumor
- Cells, Cultured
- Cricetinae
- Cricetulus
- Crystallography, X-Ray
- Drug Discovery
- GTP-Binding Proteins/metabolism
- Humans
- Magnetic Resonance Spectroscopy
- Male
- Mice, Inbred C57BL
- Models, Chemical
- Models, Molecular
- Molecular Structure
- Neurocognitive Disorders/drug therapy
- Neurocognitive Disorders/metabolism
- Permeability
- Phenyl Ethers/chemistry
- Phenyl Ethers/pharmacokinetics
- Phenyl Ethers/therapeutic use
- Propanolamines/chemistry
- Propanolamines/pharmacokinetics
- Propanolamines/therapeutic use
- Protein Binding
- Rats, Sprague-Dawley
- Receptors, Adrenergic, beta-1/chemistry
- Receptors, Adrenergic, beta-1/metabolism
- Structure-Activity Relationship
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Affiliation(s)
- Bitna Yi
- Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, California, United States of America
| | - Alam Jahangir
- Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, California, United States of America
| | - Andrew K. Evans
- Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, California, United States of America
| | - Denise Briggs
- Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, California, United States of America
| | - Kristine Ravina
- Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, California, United States of America
| | - Jacqueline Ernest
- Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, California, United States of America
| | - Amir B. Farimani
- Department of Chemistry, Stanford University, Stanford, California, United States of America
| | - Wenchao Sun
- Biomaterials and Advanced Drug Delivery Laboratory, Stanford University School of Medicine, Palo Alto, California, United States of America
| | - Jayakumar Rajadas
- Biomaterials and Advanced Drug Delivery Laboratory, Stanford University School of Medicine, Palo Alto, California, United States of America
| | - Michael Green
- Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, California, United States of America
| | - Evan N. Feinberg
- Department of Chemistry, Stanford University, Stanford, California, United States of America
| | - Vijay S. Pande
- Department of Chemistry, Stanford University, Stanford, California, United States of America
| | - Mehrdad Shamloo
- Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, California, United States of America
- * E-mail:
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Victoni T, Salvator H, Abrial C, Brollo M, Porto LCS, Lagente V, Naline E, Grassin-Delyle S, Devillier P. Human lung and monocyte-derived macrophages differ with regard to the effects of β 2-adrenoceptor agonists on cytokine release. Respir Res 2017. [PMID: 28637505 PMCID: PMC5480184 DOI: 10.1186/s12931-017-0613-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Background β2-adrenoceptor agonists have been shown to reduce the lipopolysaccharide (LPS)-induced cytokine release by human monocyte-derived macrophages (MDMs). We compare the expression of β2-adrenoceptors and the inhibitory effect of formoterol and salmeterol on the LPS-induced release of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and a range of chemokines (CCL2, 3, 4, and IL-8) by human lung macrophages (LMs) and MDMs. Methods LMs were isolated from patients undergoing resection and MDMs were obtained from blood monocytes in the presence of GM-CSF. LMs and MDMs were incubated in the absence or presence of formoterol or salmeterol prior to stimulation with LPS. The effects of formoterol were also assessed in the presence of the phosphodiesterase inhibitor roflumilast. Results LPS-induced cytokine production was higher in LMs than in MDMs. Salmeterol and formoterol exerted an inhibitory effect on the LPS-induced production of TNF-α, IL-6, CCL2, CCL3, and CCL4 in MDMs. In contrast, the β2-adrenoceptor agonists were devoid of any effect on LMs - even in the presence of roflumilast. The expression of β2-adrenergic receptors was detected on Western blots in MDMs but not in LMs. Conclusions Concentrations of β2-adrenoceptor agonists that cause relaxation of the human bronchus can inhibit cytokine production by LPS-stimulated MDMs but not by LMs. Electronic supplementary material The online version of this article (doi:10.1186/s12931-017-0613-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Tatiana Victoni
- Laboratory of Histocompatibility and Cryopresevation, Laboratory of Tissue Repair, Rio de Janeiro, Brazil.,Laboratory of Research in Respiratory Pharmacology-UPRES EA220, UFR Sciences de la Santé Simone Veil, Université Versailles Saint-Quentin, Université Paris-Saclay, 11, rue Guillaume Lenoir, F-92150, Suresnes, France
| | - Hélène Salvator
- Laboratory of Research in Respiratory Pharmacology-UPRES EA220, UFR Sciences de la Santé Simone Veil, Université Versailles Saint-Quentin, Université Paris-Saclay, 11, rue Guillaume Lenoir, F-92150, Suresnes, France.,Department of Airway Diseases, Foch Hospital, Suresnes, France
| | - Charlotte Abrial
- Laboratory of Research in Respiratory Pharmacology-UPRES EA220, UFR Sciences de la Santé Simone Veil, Université Versailles Saint-Quentin, Université Paris-Saclay, 11, rue Guillaume Lenoir, F-92150, Suresnes, France
| | - Marion Brollo
- Laboratory of Research in Respiratory Pharmacology-UPRES EA220, UFR Sciences de la Santé Simone Veil, Université Versailles Saint-Quentin, Université Paris-Saclay, 11, rue Guillaume Lenoir, F-92150, Suresnes, France
| | | | - Vincent Lagente
- Nutrition Metabolisms and Cancer, INSERM, INRA, Université Rennes 1, Université Bretagne Loire, Rennes, France
| | - Emmanuel Naline
- Laboratory of Research in Respiratory Pharmacology-UPRES EA220, UFR Sciences de la Santé Simone Veil, Université Versailles Saint-Quentin, Université Paris-Saclay, 11, rue Guillaume Lenoir, F-92150, Suresnes, France.,Department of Airway Diseases, Foch Hospital, Suresnes, France
| | - Stanislas Grassin-Delyle
- Department of Airway Diseases, Foch Hospital, Suresnes, France.,INSERM UMR1173 & Mass Spectrometry Facility, UFR Sciences de la Santé Simone Veil, Université Versailles Saint-Quentin, Université Paris-Saclay, Montigny-le-Bretonneux, France
| | - Philippe Devillier
- Laboratory of Research in Respiratory Pharmacology-UPRES EA220, UFR Sciences de la Santé Simone Veil, Université Versailles Saint-Quentin, Université Paris-Saclay, 11, rue Guillaume Lenoir, F-92150, Suresnes, France. .,Department of Airway Diseases, Foch Hospital, Suresnes, France.
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6
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Gill SK, Marriott HM, Suvarna SK, Peachell PT. Evaluation of the anti-inflammatory effects of β-adrenoceptor agonists on human lung macrophages. Eur J Pharmacol 2016; 793:49-55. [PMID: 27832943 DOI: 10.1016/j.ejphar.2016.11.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Revised: 10/31/2016] [Accepted: 11/02/2016] [Indexed: 12/21/2022]
Abstract
The principal mechanism by which bronchodilator β-adrenoceptor agonists act is to relax airways smooth muscle although they may also be anti-inflammatory. However, the extent of anti-inflammatory activity and the cell types affected by these agonists are uncertain. The purpose of this study was to evaluate whether β-adrenoceptor agonists prevent pro-inflammatory cytokine generation from activated human lung macrophages. Macrophages were isolated and purified from human lung. The cells were pre-treated with both short-acting (isoprenaline, salbutamol, terbutaline) and long-acting (formoterol, salmeterol, indacaterol) β-agonists before activation with lipopolysaccharide (LPS) to induce cytokine (TNFα, IL-6, IL-8 and IL-10) generation. The experiments showed that short-acting β-agonists were poor inhibitors of cytokine generation. Of the long-acting β-agonists studied, formoterol was also a weak inhibitor of cytokine generation whereas only indacaterol and salmeterol showed moderate inhibitory activity. Further experiments using the β2-adrenoceptor antagonist ICI-118,551 suggested that the effects of indacaterol were likely to be mediated by β2-adrenoceptors whereas those of salmeterol were not. These findings were corroborated by functional desensitization studies in which the inhibitory effects of indacaterol appeared to be receptor-mediated whereas those of salmeterol were not. Taken together, the data indicate that the anti-inflammatory effects of β-adrenoceptor agonists on human lung macrophages are modest.
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Affiliation(s)
- Sharonjit K Gill
- Academic Unit of Respiratory Medicine, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, The Medical School (Floor L), Beech Hill Road, Sheffield S10 2RX, UK
| | - Helen M Marriott
- Academic Unit of Respiratory Medicine, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, The Medical School (Floor L), Beech Hill Road, Sheffield S10 2RX, UK
| | - S Kim Suvarna
- Histopathology Department, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, UK
| | - Peter T Peachell
- Academic Unit of Respiratory Medicine, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, The Medical School (Floor L), Beech Hill Road, Sheffield S10 2RX, UK.
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Ng TM, Toews ML. Impaired norepinephrine regulation of monocyte inflammatory cytokine balance in heart failure. World J Cardiol 2016; 8:584-589. [PMID: 27847559 PMCID: PMC5088364 DOI: 10.4330/wjc.v8.i10.584] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Revised: 07/27/2016] [Accepted: 08/17/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the effect of norepinephrine on inflammatory cytokine expression in ex vivo human monocytes and monocytic THP-1 cells. METHODS For human monocyte studies, cells were isolated from 12 chronic heart failure (HF) (66 ± 12 years, New York Heart Association functional class III-IV, left ventricular ejection fraction 22% ± 9%) and 14 healthy subjects (66 ± 12 years). Monocytes (1 × 106/mL) were incubated with lipopolysaccharide (LPS) 100 ng/mL, LPS + norepinephrine (NE) 10-6 mol/L or neither (control) for 4 h. Tumor necrosis factor-alpha (TNFα) and interleukin-10 (IL-10) production were determined by ELISA. Relative contribution of α- and β-adrenergic receptor subtypes on immunomodulatory activity of NE was assessed in LPS-stimulated THP-1 cells incubated with NE, the α-selective agonist phenylephrine (PE), and the β-selective agonist isoproterenol (IPN). NE-pretreated THP-1 cells were also co-incubated with the β-selective antagonist propranolol (PROP), α2-selective antagonist yohimbine (YOH) or the α1-selective antagonist prazosin (PRAZ). RESULTS Basal TNFα concentrations were higher in HF vs healthy subjects (6.3 ± 3.3 pg/mL vs 2.5 ± 2.6 pg/mL, P = 0.004). Norepinephrine's effect on TNFα production was reduced in HF (-41% ± 17% HF vs -57% ± 9% healthy, P = 0.01), and proportionately with NYHA FC. Increases in IL-10 production by NE was also attenuated in HF (16% ± 18% HF vs 38% ± 23% healthy, P = 0.012). In THP-1 cells, NE and IPN, but not PE, induced a dose-dependent suppression of TNFα. Co-incubation with NE and antagonists revealed a dose-dependent inhibition of the NE suppression of TNFα by PROP, but not by YOH or PRAZ. Dose-dependent increases in IL-10 production were seen with NE and IPN, but not with PE. This effect was also antagonized by PROP but not by YOH or PRAZ. Pretreatment of cells with IPN attenuated the effects of NE and IPN, but did not induce a response to PE. CONCLUSION NE regulation of monocyte inflammatory cytokine production may be reduced in moderate-severe HF, and may be mediated through β-adrenergic receptors.
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Affiliation(s)
- Tien Mh Ng
- Tien MH Ng, Myron L Toews, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Myron L Toews
- Tien MH Ng, Myron L Toews, University of Nebraska Medical Center, Omaha, NE 68198, United States
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8
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Werners AH. Treatment of endotoxaemia and septicaemia in the equine patient. J Vet Pharmacol Ther 2016; 40:1-15. [PMID: 27452161 DOI: 10.1111/jvp.12329] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Accepted: 05/02/2016] [Indexed: 12/27/2022]
Abstract
Endotoxins, constituents of the cell wall of gram-positive and gram-negative bacteria, regularly result in severe illness and death in horses. In endotoxaemia, these constituents are present in the systemic circulation; in septicaemia, whole microbes invade normally sterile parts of the body. Interaction of these endotoxins with pathogen recognition receptors leads to an inflammatory response that cannot always be sufficiently contained and hence needs direct treatment. Over the last decennia, our understanding of the pathophysiology of endotoxaemia and septicaemia has significantly increased. Based on improved understanding of the interaction between receptors and endotoxins as well as the subsequent downstream signalling pathways, new therapeutic targets have been identified in laboratory animal species and humans. Important species differences in the recognition of endotoxins and pathogens by their receptors as well as the inflammatory response to receptor activation hamper extrapolation of this information to the horse (and other species). Historically, horses with endotoxaemia and septicaemia have been treated mainly symptomatically and supportively. Based on the identified therapeutic targets, this review describes the current knowledge of the treatment for endotoxaemia and septicaemia in the horse with reference to the findings in other animal species and humans.
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Affiliation(s)
- A H Werners
- Department of Anatomy, Physiology and Pharmacology, School of Veterinary Medicine, St. George's University, True Blue Campus, St. George's, Grenada, West-Indies
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9
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Baars A, Oosting A, Knol J, Garssen J, van Bergenhenegouwen J. The Gut Microbiota as a Therapeutic Target in IBD and Metabolic Disease: A Role for the Bile Acid Receptors FXR and TGR5. Microorganisms 2015; 3:641-66. [PMID: 27682110 PMCID: PMC5023267 DOI: 10.3390/microorganisms3040641] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Accepted: 10/01/2015] [Indexed: 12/18/2022] Open
Abstract
The gut microbiota plays a crucial role in regulating many physiological systems of the host, including the metabolic and immune system. Disturbances in microbiota composition are increasingly correlated with disease; however, the underlying mechanisms are not well understood. Recent evidence suggests that changes in microbiota composition directly affect the metabolism of bile salts. Next to their role in digestion of dietary fats, bile salts function as signaling molecules for bile salt receptors such as Farnesoid X receptor (FXR) and G protein-coupled bile acid receptor (TGR5). Complementary to their role in metabolism, FXR and TGR5 are shown to play a role in intestinal homeostasis and immune regulation. This review presents an overview of evidence showing that changes in bile salt pool and composition due to changes in gut microbial composition contribute to the pathogenesis of inflammatory bowel disease and metabolic disease, possibly through altered activation of TGR5 and FXR. We further discuss how dietary interventions, such as pro- and synbiotics, may be used to treat metabolic disease and inflammatory bowel disease (IBD) through normalization of bile acid dysregulation directly or indirectly through normalization of the intestinal microbiota.
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Affiliation(s)
| | | | - Jan Knol
- Nutricia Research, 3584 CT, Utrecht, The Netherlands.
- Laboratory of Microbiology, Wageningen University, 6703 HB, Wageningen, The Netherlands.
| | - Johan Garssen
- Nutricia Research, 3584 CT, Utrecht, The Netherlands.
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG, Utrecht, The Netherlands.
| | - Jeroen van Bergenhenegouwen
- Nutricia Research, 3584 CT, Utrecht, The Netherlands.
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG, Utrecht, The Netherlands.
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10
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Wex E, Kollak I, Duechs MJ, Naline E, Wollin L, Devillier P. The long-acting β2 -adrenoceptor agonist olodaterol attenuates pulmonary inflammation. Br J Pharmacol 2015; 172:3537-47. [PMID: 25824824 PMCID: PMC4507158 DOI: 10.1111/bph.13143] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Revised: 03/05/2015] [Accepted: 03/23/2015] [Indexed: 01/04/2023] Open
Abstract
Background and Purpose β2-adrenoceptor agonists are widely used in the management of obstructive airway diseases. Besides their bronchodilatory effect, several studies suggest inhibitory effects on various aspects of inflammation. The aim of our study was to determine the efficacy of the long-acting β2-adrenoceptor agonist olodaterol to inhibit pulmonary inflammation and to elucidate mechanism(s) underlying its anti-inflammatory actions. Experimental Approach Olodaterol was tested in murine and guinea pig models of cigarette smoke- and LPS-induced lung inflammation. Furthermore, effects of olodaterol on the LPS-induced pro-inflammatory mediator release from human parenchymal explants, CD11b adhesion molecule expression on human granulocytes TNF-α release from human whole blood and on the IL-8-induced migration of human peripheral blood neutrophils were investigated. Key Results Olodaterol dose-dependently attenuated cell influx and pro-inflammatory mediator release in murine and guinea pig models of pulmonary inflammation. These anti-inflammatory effects were observed at doses relevant to their bronchodilatory efficacy. Mechanistically, olodaterol attenuated pro-inflammatory mediator release from human parenchymal explants and whole blood and reduced expression of CD11b adhesion molecules on granulocytes, but without direct effects on IL-8-induced neutrophil transwell migration. Conclusions and Implications This is the first evidence for the anti-inflammatory efficacy of a β2-adrenoceptor agonist in models of lung inflammation induced by cigarette smoke. The long-acting β2-adrenoceptor agonist olodaterol attenuated pulmonary inflammation through mechanisms that are separate from direct inhibition of bronchoconstriction. Furthermore, the in vivo data suggest that the anti-inflammatory properties of olodaterol are maintained after repeated dosing for 4 days.
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Affiliation(s)
- Eva Wex
- Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - Ines Kollak
- Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - Matthias J Duechs
- Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - Emmanuel Naline
- UPRES EA 220 and Clinical Research Department, Foch Hospital, University of Versailles Saint-Quentin, Suresnes, France
| | - Lutz Wollin
- Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - Philippe Devillier
- UPRES EA 220 and Clinical Research Department, Foch Hospital, University of Versailles Saint-Quentin, Suresnes, France
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11
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Seo HS. Appropriate candidates for statin use in heart failure. Korean J Intern Med 2014; 29:730-4. [PMID: 25378970 PMCID: PMC4219961 DOI: 10.3904/kjim.2014.29.6.730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Accepted: 10/22/2014] [Indexed: 11/27/2022] Open
Affiliation(s)
- Hong Seog Seo
- Cardiovascular Center, Korea University Guro Hospital, Seoul, Korea
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12
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Greig CA, Johns N, Gray C, MacDonald A, Stephens NA, Skipworth RJE, Fallon M, Wall L, Fox GM, Fearon KCH. Phase I/II trial of formoterol fumarate combined with megestrol acetate in cachectic patients with advanced malignancy. Support Care Cancer 2014; 22:1269-75. [DOI: 10.1007/s00520-013-2081-3] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2013] [Accepted: 11/26/2013] [Indexed: 11/25/2022]
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13
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Li Y, Jadhav K, Zhang Y. Bile acid receptors in non-alcoholic fatty liver disease. Biochem Pharmacol 2013; 86:1517-24. [PMID: 23988487 DOI: 10.1016/j.bcp.2013.08.015] [Citation(s) in RCA: 101] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2013] [Revised: 08/14/2013] [Accepted: 08/15/2013] [Indexed: 12/17/2022]
Abstract
Accumulating data have shown that bile acids are important cell signaling molecules, which may activate several signaling pathways to regulate biological processes. Bile acids are endogenous ligands for the farnesoid X receptor (FXR) and TGR5, a G-protein coupled receptor. Gain- and loss-of-function studies have demonstrated that both FXR and TGR5 play important roles in regulating lipid and carbohydrate metabolism and inflammatory responses. Importantly, activation of FXR or TGR5 lowers hepatic triglyceride levels and inhibits inflammation. Such properties of FXR or TGR5 have indicated that these two bile acid receptors are ideal targets for treatment of non-alcoholic fatty liver disease, one of the major health concerns worldwide. In this article, we will focus on recent advances on the role of both FXR and TGR5 in regulating hepatic triglyceride metabolism and inflammatory responses under normal and disease conditions.
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Affiliation(s)
- Yuanyuan Li
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH 44272, United States
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14
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Stepanov V, Stankov K, Mikov M. The bile acid membrane receptor TGR5: a novel pharmacological target in metabolic, inflammatory and neoplastic disorders. J Recept Signal Transduct Res 2013; 33:213-23. [PMID: 23782454 DOI: 10.3109/10799893.2013.802805] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
TGR5 is the G-protein-coupled bile acid-activated receptor, found in many human and animal tissues. Considering different endocrine and paracrine functions of bile acids, the current review focuses on the role of TGR5 as a novel pharmacological target in the metabolic syndrome and related disorders, such as diabetes, obesity, atherosclerosis, liver diseases and cancer. TGR5 ligands improve insulin sensitivity and glucose homeostasis through the secretion of incretins. The bile acid/TGR5/cAMP signaling pathway increases energy expenditure in brown adipose tissue and skeletal muscle. Activation of TGR5 in macrophages inhibits production of proinflammatory cytokines and attenuates the development of atherosclerosis. This receptor has been detected in many cell types of the liver where it has anti-inflammatory effects, thus reducing liver steatosis and damage. TGR5 also modulates hepatic microcirculation and fluid secretion in the biliary tree. In cell culture models TGR5 has been linked to signaling pathways involved in metabolism, cell survival, proliferation and apoptosis, which suggest a possible role of TGR5 in cancer development. Despite the fact that TGR5 ligands may represent novel drugs for prevention and treatment of different aspects of the metabolic syndrome, clinical studies are awaited with the perspective that they will complete TGR5 biology and identify efficient and safe TGR5 agonists.
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Affiliation(s)
- Vanesa Stepanov
- Department of Pharmacology, Clinical Pharmacology and Toxicology, University of Novi Sad, Novi Sad, Serbia.
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15
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Cudmore LA, Muurlink T, Whittem T, Bailey SR. Effects of oral clenbuterol on the clinical and inflammatory response to endotoxaemia in the horse. Res Vet Sci 2013; 94:682-6. [PMID: 23462621 DOI: 10.1016/j.rvsc.2013.01.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2012] [Revised: 01/04/2013] [Accepted: 01/12/2013] [Indexed: 10/27/2022]
Abstract
Pro-inflammatory cytokines, such as IL-1β and TNFα, play a major role in activating leukocytes and endothelial cells during the systemic inflammatory response to endotoxin in the horse. β2 agonist drugs, such as clenbuterol, inhibit leukocyte activation. This study aimed to determine the effects of oral clenbuterol on clinical and leukocyte responses, including production of TNFα, in an in vivo endotoxin challenge model. In a randomised crossover design, horses received either clenbuterol or a placebo product prior to the administration of low dose endotoxin (30 ng/kg over 30 min). Clinical signs were measured and leukocyte counts and serial blood samples were obtained over 6 h. Pre-treatment with oral clenbuterol (0.8 μg/kg) significantly reduced (P=0.046) the peak rectal temperature and the peak plasma TNFα concentration (P=0.026) following endotoxin challenge. These data suggest that oral clenbuterol at the therapeutic dose has anti-inflammatory effects in horses challenged with a low dose of endotoxin.
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Affiliation(s)
- L A Cudmore
- University of Melbourne Equine Centre, 250 Princes Highway, Werribee, Victoria 3030, Australia
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16
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Ara T, Fujinami Y, Urano H, Hirai K, Hatori T, Miyazawa H. Protein kinase A enhances lipopolysaccharide-induced IL-6, IL-8, and PGE₂ production by human gingival fibroblasts. J Negat Results Biomed 2012; 11:10. [PMID: 22452847 PMCID: PMC3355011 DOI: 10.1186/1477-5751-11-10] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2012] [Accepted: 03/27/2012] [Indexed: 01/18/2023] Open
Abstract
OBJECTIVE Periodontal disease is accompanied by inflammation of the gingiva and destruction of periodontal tissues, leading to alveolar bone loss in severe clinical cases. Interleukin (IL)-6, IL-8, and the chemical mediator prostaglandin E₂ (PGE₂) are known to play important roles in inflammatory responses and tissue degradation. Recently, we reported that the protein kinase A (PKA) inhibitor H-89 suppresses lipopolysaccharide (LPS)-induced IL-8 production by human gingival fibroblasts (HGFs). In the present study, the relevance of the PKA activity and two PKA-activating drugs, aminophylline and adrenaline, to LPS-induced inflammatory cytokines (IL-6 and IL-8) and PGE₂ by HGFs were examined. METHODS HGFs were treated with LPS from Porphyromonas gingivalis and H-89, the cAMP analog dibutyryl cyclic AMP (dbcAMP), aminophylline, or adrenaline. After 24 h, IL-6, IL-8, and PGE₂ levels were evaluated by ELISA. RESULTS H-89 did not affect LPS-induced IL-6 production, but suppressed IL-8 and PGE₂ production. In contrast, dbcAMP significantly increased LPS-induced IL-6, IL-8, and PGE₂ production. Up to 10 μg/ml of aminophylline did not affect LPS-induced IL-6, IL-8, or PGE₂ production, but they were significantly increased at 100 μg/ml. Similarly, 0.01 μg/ml of adrenaline did not affect LPS-induced IL-6, IL-8, or PGE₂ production, but they were significantly increased at concentrations of 0.1 and 1 μg/ml. In the absence of LPS, H-89, dbcAMP, aminophylline, and adrenaline had no relevance to IL-6, IL-8, or PGE₂ production. CONCLUSION These results suggest that the PKA pathway, and also PKA-activating drugs, enhance LPS-induced IL-6, IL-8, and PGE₂ production by HGFs. However, aminophylline may not have an effect on the production of these molecules at concentrations used in clinical settings (8 to 20 μg/ml in serum). These results suggest that aminophylline does not affect inflammatory responses in periodontal disease.
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Affiliation(s)
- Toshiaki Ara
- Department of Pharmacology, Matsumoto Dental University, 1780 Gobara Hirooka, Shiojiri, Nagano 399-0781, Japan
| | - Yoshiaki Fujinami
- Department of Pharmacology, Matsumoto Dental University, 1780 Gobara Hirooka, Shiojiri, Nagano 399-0781, Japan
| | - Hiroko Urano
- Institute for Oral Science, Matsumoto Dental University, 1780 Gobara Hirooka, Shiojiri, Nagano 399-0781, Japan
| | - Kaname Hirai
- Department of Oral Microbiology, Matsumoto Dental University, 1780 Gobara Hirooka, Shiojiri, Nagano 399-0781, Japan
| | - Toshimi Hatori
- Department of Pharmacology, Matsumoto Dental University, 1780 Gobara Hirooka, Shiojiri, Nagano 399-0781, Japan
| | - Hiroo Miyazawa
- Department of Oral Health Promotion, Graduate School of Oral Medicine, Matsumoto Dental University, 1780 Gobara Hirooka, Shiojiri, Nagano 399-0781, Japan
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17
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Significance of the adrenal and sympathetic response to burn injury. TOTAL BURN CARE 2012. [DOI: 10.1016/b978-1-4377-2786-9.00024-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
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Hiraguchi Y, Tanida H, Hosoki K, Nagao M, Tokuda R, Fujisawa T. Inhibition of eosinophil activation mediated by a Toll-like receptor 7 ligand with a combination of procaterol and budesonide. Int Arch Allergy Immunol 2011; 155 Suppl 1:85-9. [PMID: 21646801 DOI: 10.1159/000327438] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Viral respiratory tract infections play an important role in the inception and exacerbation of asthma. Eosinophils, major effector cells in asthma, often accumulate in the airways during viral infections and are possibly activated by respiratory RNA viruses through Toll-like receptor (TLR) 7. We investigated the effect of a β(2)-agonist, i.e. procaterol, and a corticosteroid, i.e. budesonide, that are commonly used for viral-induced asthma, on TLR7 ligand-induced activation of eosinophils in vitro. METHODS Purified peripheral blood eosinophils were incubated with procaterol and/or budesonide and stimulated with a TLR7 ligand, i.e. R-837. Expression of CD11b was analyzed by flow cytometry. Superoxide generation was measured via the cytochrome C reduction method. IL-8 in the supernatants was assayed by ELISA. RESULTS Although procaterol or budesonide alone did not inhibit R-837-induced CD11b expression, combinations of the 2 drugs significantly inhibited CD11b. Likewise, the combinations significantly inhibited O(2)(-) generation at low concentrations. Budesonide significantly inhibited R-837-induced IL-8 production in a concentration-dependent manner, and procaterol potentiated inhibition by budesonide although single-agent procaterol had no effect. CONCLUSION A combination of procaterol and budesonide inhibits the TLR7-mediated effector function of eosinophils, indicating their possible anti-inflammatory effect for virus-induced asthma.
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Affiliation(s)
- Yukiko Hiraguchi
- Institute for Clinical Research, Mie National Hospital, Tsu, Japan
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19
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The bile acid membrane receptor TGR5 as an emerging target in metabolism and inflammation. J Hepatol 2011; 54:1263-72. [PMID: 21145931 PMCID: PMC3650458 DOI: 10.1016/j.jhep.2010.12.004] [Citation(s) in RCA: 316] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2010] [Revised: 11/11/2010] [Accepted: 12/02/2010] [Indexed: 02/08/2023]
Abstract
Bile acids (BAs) are amphipathic molecules that facilitate the uptake of lipids, and their levels fluctuate in the intestine as well as in the blood circulation depending on food intake. Besides their role in dietary lipid absorption, bile acids function as signaling molecules capable to activate specific receptors. These BA receptors are not only important in the regulation of bile acid synthesis and their metabolism, but also regulate glucose homeostasis, lipid metabolism, and energy expenditure. These processes are important in diabetes and other facets of the metabolic syndrome, which represents a considerable increasing health burden. In addition to the function of the nuclear receptor FXRα in regulating local effects in the organs of the enterohepatic axis, increasing evidence points to a crucial role of the G-protein coupled receptor (GPCR) TGR5 in mediating systemic actions of BAs. Here we discuss the current knowledge on BA receptors, with a strong focus on the cell membrane receptor TGR5, which emerges as a valuable target for intervention in metabolic diseases.
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Abstract
Inflammation can cause damage and even death. What controls this primitive and potentially lethal innate immune response to injury and infection? Molecular and neurophysiological studies during the past decade have revealed a pivotal answer: immunity is coordinated by neural circuits that operate reflexively. The afferent arc of the reflex consists of nerves that sense injury and infection. This activates efferent neural circuits, including the cholinergic anti-inflammatory pathway, that modulate immune responses and the progression of inflammatory diseases. It might be possible to develop therapeutics that target neural networks for the treatment of inflammatory disorders.
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21
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22
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Ramos BP, Colgan LA, Nou E, Arnsten AF. Beta2 adrenergic agonist, clenbuterol, enhances working memory performance in aging animals. Neurobiol Aging 2008; 29:1060-9. [PMID: 17363115 PMCID: PMC3154024 DOI: 10.1016/j.neurobiolaging.2007.02.003] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2006] [Revised: 01/29/2007] [Accepted: 02/05/2007] [Indexed: 11/29/2022]
Abstract
Previous studies using a mixed beta1 and beta2 adrenergic antagonist, propanolol, have indicated that beta adrenoceptors have little effect on the cognitive functioning of the prefrontal cortex. However, recent studies have suggested that endogenous stimulation of beta1 adrenoceptors impairs working memory in both rats and monkeys. Since propanolol has no effect on cognition, we hypothesized that activation of beta2 adrenoceptors might improve performance in a working memory task. We tested this hypothesis by observing the effects of the beta2 agonist, clenbuterol, on spatial working memory performance. Clenbuterol was either infused directly into the prefrontal cortex (rats) or administered systemically (monkeys). Results demonstrated that clenbuterol improved performance in many young and aged rats and monkeys who performed poorly under control conditions. Actions at beta2 adrenoceptors were confirmed by challenging the clenbuterol response with the beta2 adrenergic antagonist, ICI 118,551. The effects of clenbuterol were not universal and depended on the cognitive status of the animal: the drug moderately improved only a subset of animals with working memory impairment.
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Affiliation(s)
- Brian P. Ramos
- Yale University School of Medicine, Department of Neurobiology, SHM C-300, 333 Cedar Street, New Haven, CT 06510, USA
| | - Leslie A. Colgan
- Yale University School of Medicine, Department of Neurobiology, SHM C-300, 333 Cedar Street, New Haven, CT 06510, USA
| | - Eric Nou
- Yale University School of Medicine, Department of Neurobiology, SHM C-300, 333 Cedar Street, New Haven, CT 06510, USA
| | - Amy F.T. Arnsten
- Yale University School of Medicine, Department of Neurobiology, SHM C-300, 333 Cedar Street, New Haven, CT 06510, USA
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Beta-adrenergic blockade exacerbates sepsis-induced changes in tumor necrosis factor alpha and interleukin-6 in skeletal muscle and is associated with impaired translation initiation. ACTA ACUST UNITED AC 2008; 64:477-86. [PMID: 18301218 DOI: 10.1097/01.ta.0000249375.43015.01] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
BACKGROUND Sepsis stimulates the sympathetic nervous system. The resultant elevation in plasma catecholamines, both norepinephrine and epinephrine (Epi), might be expected to alter the expression of inflammatory cytokines, which may directly or indirectly influence muscle protein balance. The purpose of this study was twofold: (1) determine whether Epi per se increases cytokine expression in skeletal muscle, and (2) determine whether beta-adrenergic blockade alters the sepsis-induced expression of inflammatory cytokines and mediators of protein balance in skeletal muscle. METHODS In the first study, rats were infused with Epi for 2 hour to increase the circulating Epi concentration to levels seen in septic animals. In the second study, sepsis was induced by cecal ligation and puncture and a nonspecific beta-adrenergic blockade produced with a continuous infusion of propranolol (PP). Tissues were obtained 24 after induction of sepsis and analyzed for tumor necrosis factor (TNF)-alpha interleukin (IL)-1beta, IL-6 mRNA and protein content. In addition, the tissue content of insulin-like growth factor (IGF)-I and various regulators of protein synthesis were assessed. RESULTS Epi acutely increased TNF-alpha IL-6 and IL-1beta mRNA content in muscle (3- to 40-fold). However, only the TNF-alpha and IL-6 protein content was increased in muscle by Epi. In the second study, beta-adrenergic blockade with PP exacerbated the sepsis-induced increase in muscle IL-6 and TNF-alpha mRNA but did not alter the increment in IL-1beta or HMGB1. Propranolol also accentuated the sepsis-induced increase in both IL-6 and TNF-alpha protein in muscle. The exaggerated muscle cytokine response in septic rats treated with PP was associated with a reduction in muscle IGF-I protein that was greater than detected in saline-infused septic rats. Finally, the combination of sepsis + PP also accentuated the sepsis-induced decrease in the phosphorylation of 4E-binding protein-1, ribosomal protein S6, and mTOR, which are key proteins controlling protein synthesis. CONCLUSIONS These results demonstrate that although Epi is capable of increasing tissue cytokines in naive rats, inhibition of the beta-adrenergic effects of catecholamines exacerbates the sepsis-induced increase of selected inflammatory cytokines. This exaggerated tissue response is associated with alterations in muscle IGF-I protein and translation initiation, which would be expected to impair tissue protein synthesis.
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El-Menyar AA. Cytokines and myocardial dysfunction: state of the art. J Card Fail 2008; 14:61-74. [PMID: 18226775 DOI: 10.1016/j.cardfail.2007.09.006] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2007] [Revised: 09/07/2007] [Accepted: 09/10/2007] [Indexed: 12/13/2022]
Abstract
BACKGROUND Myocardial dysfunction has been associated with inflammation and cytokine modulation. OBJECTIVES The study objective was to understand the role of cytokines in the pathophysiology and management of myocardial dysfunction. METHODS Heart failure has been revisited with revision of the pertinent published articles in the Medline, Scopus, Cochrane Database of Systematic Reviews, and EBSCO Host research. RESULTS For the proinflammatory cytokines, illumination of this important point requires further diagnostic and therapeutic investigations. Data on chronic heart failure are not so reassuring; therefore, patients with advanced heart failure should not be treated with anticytokines at this time. CONCLUSION Further studies are warranted to pave the way for introducing cytokine and immunomodulation therapy at the optimal and appropriate time.
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Cazzola M, Ciaprini C, Page CP, Matera MG. Targeting systemic inflammation: novel therapies for the treatment of chronic obstructive pulmonary disease. Expert Opin Ther Targets 2007; 11:1273-86. [PMID: 17907958 DOI: 10.1517/14728222.11.10.1273] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The increasing evidence that inflammation in the lungs leads to the structural changes observed in chronic obstructive pulmonary disease, whereas extrapulmonary symptoms and comorbidities may be systemic manifestations of these inflammatory processes, highlights an urgent need to discover novel, effective anti-inflammatory treatments for this disease. Some studies are suggesting that, by decreasing dynamic hyperinflation, bronchodilators might reduce systemic inflammation; inhaled corticosteroids and their combination with long-acting beta2-agonists might contribute to this goal. Even so, the opinion that suppression of the inflammatory response might improve systemic complications is stimulating a search for novel anti-inflammatory therapies. Many drugs include those that inhibit the recruitment and activation of inflammatory cells and/or antagonise their products. However, many of these therapeutic strategies are not specific for neutrophilic inflammation because they affect other cell types, thus, it is difficult to interpret whether any clinical benefit observed is a result of a reduction in airway neutrophils. In any case, there is some evidence that drugs used to treat a co-morbid condition, such as statins, angiotensin converting enzyme (ACE) inhibitors and angiontensin II type 1 (AT1) receptor blockers as well as glycosaminoglycans and peroxisome proliferator-activated receptor (PPAR) agonists, might benefit chronic obstructive pulmonary disease patients because they deal with the extrapulmonary, systemic component of chronic obstructive pulmonary disease.
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Affiliation(s)
- Mario Cazzola
- Associate Professor of Respiratory Medicine, Universitá di Roma Tor Vergata, Dipartimento di Medicina Interna, Via Montpellier 1, 00133 Roma, Italy.
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Yang FL, Li CH, Hsu BG, Tsai NM, Lin SZ, Harn HJ, Chen HI, Liao KW, Lee RP. The reduction of tumor necrosis factor-alpha release and tissue damage by pentobarbital in the experimental endotoxemia model. Shock 2007; 28:309-16. [PMID: 17545946 DOI: 10.1097/shk.0b013e31803dd04d] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Sepsis is the leading cause of death for intensive care patients. Lipopolysaccharide (LPS) administration to animals under anesthesia is a strategy for the study of uncontrolled release of proinflammatory cytokines. Anesthetics have been indicated that they can specially affect immune responses, such as the inflammatory response. Pentobarbital is an anesthetic used mainly in animal studies. Thus, the effect of pentobarbital on tumor necrosis factor-alpha (TNF-alpha) release was determined. The results revealed that pentobarbital suppressed the expression of TNF-alpha mRNA and its proteins, which may result from the decrease in the activities of nuclear factor-kappaB and activator protein 1 and the reduction of the expression of p38 mitogen-activated protein kinase by pentobarbital. After the inhibitory activity of the pentobarbital for TNF-alpha release was proven in vivo, the cytotoxic effects of LPS were examined in vivo with or without pentobarbital treatments. In vivo results indicated that plasma levels of alanine aminotransferase, aspartate aminotransferase, lactic dehydrogenase, creatine kinase, serum urea nitrogen, and amylase decreased dramatically in the anesthetic group with pentobarbital administration. Finally, the effect of pentobarbital on TNF-alpha-related cell death was monitored in vitro, and the results indicated the pentobarbital could directly enhance the viabilities of cells under the treatment of TNF-alpha and protected cells from apoptosis induced by deferoxamine mesylate-induced hypoxia. These results suggest that pentobarbital significantly influences the LPS-induced inflammatory response and protects cells from death directly and indirectly induced by TNF-alpha. The information provides a perspective to re-evaluate the results of the experiments in which animals were anesthetized with pentobarbital. The anti-inflammatory effects of the drugs may have been caused by the synergistic effect of pentobarbital.
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Affiliation(s)
- Fwu Lin Yang
- Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan, Republic of China
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Boost KA, Flondor M, Hofstetter C, Platacis I, Stegewerth K, Hoegl S, Nguyen T, Muhl H, Zwissler B. The beta-adrenoceptor antagonist propranolol counteracts anti-inflammatory effects of isoflurane in rat endotoxemia. Acta Anaesthesiol Scand 2007; 51:900-8. [PMID: 17635398 DOI: 10.1111/j.1399-6576.2007.01363.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
BACKGROUND Recent studies suggest that volatile anaesthetics have anti-inflammatory and preconditioning properties and that beta-adrenoceptors are involved in the signalling pathways for these effects. Concurrently, the blockade of beta-adrenoceptors has been shown to augment the release of inflammatory mediators in response to pro-inflammatory stimuli. We therefore aimed to investigate whether the beta-adrenoceptor antagonist propranolol might modulate the anti-inflammatory effects of isoflurane on the systemic and pulmonary release of pro-inflammatory cytokines in endotoxemic rats. METHODS Forty anaesthetized and ventilated Sprague-Dawley rats were randomly treated as follows. Lipopolysaccharide (LPS) only (n = 8), endotoxemia with LPS [5 mg/kg, intravenously (i.v.)]. LPS-isoflurane (n = 8): endotoxemia and continuous inhalation of 1 minimum alveolar concentration (MAC) of isoflurane. LPS-isoflurane-propranolol (n = 8): administration of propranolol (3 mg/kg) before continuous inhalation of isoflurane and induction of endotoxemia. LPS-propranolol (n = 8): administration of propranolol (3 mg/kg) before endotoxemia without inhalation of isoflurane. Sham (n = 8): control-group only with surgical preparation. After 4 h of endotoxemia, levels of tumour necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-10 (IL-10) in plasma and bronchoalveolar fluid (BALF) were analysed. Release of nitric oxide (NO) and amount of inducible nitric oxide synthase (iNOS) protein in alveolar macrophages was measured by Griess assay or determined by Western Blotting, respectively. RESULTS Inhalation of isoflurane reduced the release of TNF-alpha (P < 0.05) and IL-1beta (P < 0.05) in plasma and IL-1beta (P < 0.05) in BALF. Co-administration of propranolol significantly inhibited these effects. During inhalation of isoflurane, the increased release of NO and iNOS protein from alveolar macrophages was also completely inhibited by propranolol. CONCLUSION Our results indicate for the first time, that blockade of beta-adrenoceptors counteracts the anti-inflammatory effects of isoflurane in endotoxemic rats.
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Affiliation(s)
- K A Boost
- Department of Anaesthesiology, Intensive Care and Pain Therapy, University Hospital of Johann Wolfgang Goethe-University Frankfurt am Main, Germany.
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Abstract
Surgical trauma and anaesthetics may cause immune suppression, predisposing patients to postoperative infections. Furthermore, stress such as surgery and pain per se is associated with immune suppression which, in animal models, leads to an increased susceptibility to infection and tumour spread. Thus, by modulating the neurohumoral stress response, anaesthesia may indirectly affect the immune system of surgical patients. In particular, regional anaesthesia attenuates this stress response and the associated effects on cellular and humoral immunity. Additionally, anaesthetics may directly affect the functions of immune-competent cells. However, the reported effects of commercial preparations of, for example, propofol, etomidate and midazolam are highly dependent on the applied solvent. Immunosuppressive effects may be particularly relevant in the intensive care unit when anaesthetics are used as long-term sedatives. There is a striking body of evidence that long-term exposure to certain sedatives is paralleled by infectious complications. On the other hand, anti-inflammatory effects of anaesthetics may be therapeutically beneficial in distinct situations such as those involving ischaemia/reperfusion injury or the systemic inflammatory response syndrome. Consequently, sedatives should be administered with careful regard to their respective potential immunomodulatory properties, the clinical situation, and the immunity status of the critically ill patient.
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Affiliation(s)
- I Kelbel
- Department of Postoperative Intensive Care Medicine, Clinic for Anaesthesiology, University Medical School, D-89070 Ulm, Germany.
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Jones SB, Muthu K, Shankar R, Gamelli RL. Significance of the adrenal and sympathetic response to burn injury. TOTAL BURN CARE 2007:343-360. [DOI: 10.1016/b978-1-4160-3274-8.50028-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
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Laengle UW, Trendelenburg AU, Markstein R, Nogues V, Provencher-Bollinger A, Roman D. GLC756 decreases TNF-alpha via an alpha2 and beta2 adrenoceptor related mechanism. Exp Eye Res 2006; 83:1246-51. [PMID: 16938291 DOI: 10.1016/j.exer.2006.07.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2006] [Revised: 07/06/2006] [Accepted: 07/07/2006] [Indexed: 11/20/2022]
Abstract
GLC756, a polyvalent anti-glaucoma drug showed in an endotoxin-induced-uveitis model (EIU) in rats a significant tumor necrosis factor-alpha (TNF-alpha) decrease in serum, indicating an additional anti-inflammatory potential of this compound. The receptors on which GLC756 binds (D1, D2, D4, alpha-1, alpha-2, 5-HT1A, 5-HT2C, 5-HT1D, 5-HT2 A, beta-1, and beta-2) were suggested to play a role. In order to identify a receptor type mediating the TNF-alpha lowering response, GLC756 was combined with various counteracting compounds (CP). For EIU, 8-week-old Lewis rats were intravenously injected at 160 microg lipopolysaccharide (LPS) from Salmonella typhimurium. Before EIU-induction animals received either one of the CP's or GLC756 alone, or GLC756 in combination with one of the CP's. TNF-alpha was determined in serum 2h post EIU-induction. Treatment with CP's alone indicated that agonistic effects on beta-2 adrenoceptors and antagonistic effects on alpha-2, 5-HT1A and 5-HT1D receptors resulted in statistically significant decreased TNF-alpha levels in comparison to the LPS-control group. In combination with GLC756, the counteracting CP's domitor (alpha-2 adrenoceptor agonist) and ICI 118551 (beta-2 adrenoceptor antagonist) inhibited completely the TNF-alpha decreasing effect of GLC756. Counteracting the 5-HT1A receptor with the 5-HT1A agonist 8-OH-DPAT could not prevent the TNF-alpha decreasing effect of GLC756. In conclusion, the antagonistic effect on alpha-2 adrenoceptors and the agonistic effect on beta-2 adrenoceptors were identified as mechanism for the TNF-alpha decreasing effect of GLC756.
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Affiliation(s)
- Ulrich W Laengle
- Department of Toxicology/Pathology, Novartis Pharma AG, MUT-2881.1.33, CH-4002 Basel, Switzerland.
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31
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Werner MFP, Souza GEP, Zampronio AR. Nimesulide-induced antipyresis in rats involves both cyclooxygenase-dependent and independent mechanisms. Eur J Pharmacol 2006; 543:181-9. [PMID: 16814279 DOI: 10.1016/j.ejphar.2006.05.029] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2005] [Revised: 03/27/2006] [Accepted: 05/19/2006] [Indexed: 10/24/2022]
Abstract
This study evaluates the antipyretic activity of nimesulide, a cyclooxygenase (COX-2) selective inhibitor in rats. The effects of nimesulide on lipopolysaccharide (LPS)-induced cerebrospinal prostaglandin E(2) (PGE(2)) and prostaglandin F(2alpha) (PGF(2alpha)) and on plasma tumor necrosis factor-alpha (TNF-alpha) levels were also evaluated. Male Wistar rats received an i.p. injection of LPS, or i.c.v. injections of interleukin-1beta (IL-1beta), interleukin-6 (IL-6), TNF-alpha, macrophage inflammatory protein-1alpha (MIP-1alpha), arachidonic acid, PGE(2), PGF(2alpha), corticotrophin-releasing factor (CRF) or endothelin-1 (ET-1). Nimesulide or indomethacin administered i.p 30 min prior LPS, IL-1beta, IL-6, TNF-alpha or arachidonic acid reduced the febrile response and PGE(2) or PGF(2alpha) levels in LPS-febrile rats but did not modify PGE(2)-induced fever. Nimesulide, but not indomethacin, reduced the fever induced by MIP-1alpha, PGF(2alpha), CRF or ET-1. Plasma TNF-alpha levels in LPS-treated rats were also reduced by nimesulide. These findings confirm that the antipyretic effect of nimesulide differs from the antipyretic scenario with the non-selective cyclooxygenase blocker indomethacin. Additional mechanisms, including inhibition of increased plasma TNF-alpha, may contribute to its antipyretic activity in rats.
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Affiliation(s)
- Maria F P Werner
- Departamento de Farmacologia, Setor de Ciências Biológicas, Universidade Federal do Paraná, Caixa Postal 19031, Curitiba, PR, 81540-970, Brazil
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Makhlouf MA, Simhan HN. Effect of tocolytics on interleukin-8 production by human amniotic and decidual cells. J Reprod Immunol 2006; 69:1-7. [PMID: 16384605 DOI: 10.1016/j.jri.2005.09.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2005] [Revised: 08/31/2005] [Accepted: 09/06/2005] [Indexed: 10/25/2022]
Abstract
Preterm labor is associated with the release of various cytokines that play an important role in its pathophysiology. In preterm labor, tocolytics are used to inhibit uterine contractions and prolong gestation. We tested the hypothesis that tocolytics alter endotoxin-induced interleukin (IL-8) production from amniotic and decidual cells in vitro. Amniotic and decidual cells were isolated from patients undergoing elective repeat cesarean section at term. Cells were grown in tissue culture flasks. Cells were subsequently incubated with 100 ng/ml of endotoxin in 24 well plates in the presence of increasing concentrations of magnesium sulfate, nifedipine and terbutaline. After 24 h, IL-8 levels in each well were measured by ELISA. Endotoxin caused a significant elevation in IL-8 production in both amniotic and decidual cells. Magnesium sulfate dose dependently inhibited the endotoxin-stimulated IL-8 production in both decidual and amniotic cells. However, nifedipine and terbutaline did not significantly affect IL-8 production in either cell type. In conclusion, magnesium sulfate differentially suppresses endotoxin-stimulated IL-8 production in amniotic and decidual cells in vitro. The cellular mechanisms of this suppression and its clinical relevance in the setting of preterm labor merit further investigation.
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Affiliation(s)
- Michel A Makhlouf
- Department of Obstetrics, Gynecology and Reproductive Sciences, Magee-Womens Hosptial, University of Pittsburgh, PA 15213, USA
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Lindberg C, Hjorth E, Post C, Winblad B, Schultzberg M. Cytokine production by a human microglial cell line: effects of beta-amyloid and alpha-melanocyte-stimulating hormone. Neurotox Res 2005; 8:267-76. [PMID: 16371321 DOI: 10.1007/bf03033980] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Senile plaques in the Alzheimer's disease (AD) are formed by aggregation of beta-amyloid (Abeta) peptide. Abeta peptide has been shown to activate microglia and stimulate their production of inflammatory factors, such as cytokines. In the AD brain, the continued presence of amyloid plaques may keep microglia persistently activated, leading to chronic inflammation in the CNS. It is well established that alpha-melanocyte-stimulating hormone (alpha-MSH) gives rise to anti-inflammatory and anti-pyretic effects. The biological activities of alpha-MSH are mediated by one or more of the melanocortin receptor (MCR) subtypes, i.e. MCR1 - MCR5. The aim of the present study was to determine the effect of alpha-MSH alone and on Abeta-activated microglial cells with regard to the secretion of inflammatory cytokines, such as interleukin-6 (IL-6), and to determine which receptor subtype mediates the effects of alpha-MSH. The human microglial cell line, CHME3, was incubated for 24 h with freshly dissolved Abeta(1-40), interferon-gamma (IFN-gamma) and/or alpha-MSH. Freshly dissolved Abeta(1-40) (5-60 microM) resulted in a dose-dependent decrease in cell viability, along with a dose-dependent increase in IL-6 release. Neither IFN-gamma nor alpha-MSH affected the Abeta-induced secretion of IL-6, but resulted in a dose-dependent increase in basal IL-6 release. Agouti, the endogenous antagonist of MCR1 and 4, further increased the alpha-MSH-induced secretion of IL-6. RT-PCR showed the expression of MCR1, MCR3, MCR4 and MCR5 mRNA. The combined data suggest that the effect of alpha-MSH in increasing IL-6 release from the human microglial cell line is mediated by MCR3 or MCR5.
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Affiliation(s)
- Catharina Lindberg
- Karolinska Institutet, Neurotec Department, Division of Experimental Geriatrics, Karolinska University Hospital Huddinge, Novum, SE-141 86 Stockholm, Sweden
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Maris NA, de Vos AF, Dessing MC, Spek CA, Lutter R, Jansen HM, van der Zee JS, Bresser P, van der Poll T. Antiinflammatory effects of salmeterol after inhalation of lipopolysaccharide by healthy volunteers. Am J Respir Crit Care Med 2005; 172:878-84. [PMID: 15994467 DOI: 10.1164/rccm.200503-451oc] [Citation(s) in RCA: 98] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
RATIONALE Salmeterol is a beta2-adrenoreceptor agonist used in the treatment of obstructive pulmonary disease. Salmeterol inhibits inflammatory responses by neutrophils and mononuclear cells in vitro and in mouse models of lung inflammation in vivo. OBJECTIVE To determine the effect of salmeterol on LPS-induced lung inflammation in humans. METHODS Thirty-two healthy subjects were enrolled in a single-blinded, placebo-controlled study. Subjects inhaled 100 microg salmeterol or placebo (t=-0.5 h) followed by 100 microg LPS or normal saline (t=0 h; n=8/group). Measurements were performed in bronchoalveolar lavage fluid and purified alveolar macrophages obtained 6 h post-challenge. MEASUREMENTS AND MAIN RESULTS Inhalation of LPS was associated with neutrophil influx, neutrophil degranulation (myeloperoxidase, bactericidal/permeability-increasing protein and elastase), release of cytokines (tumor necrosis factor alpha and interleukin 6) and chemokines (interleukin 8, epithelial cell-derived neutrophil attractant 78, macrophage inflammatory proteins 1alpha and 1beta), activation of alveolar macrophages (upregulation of HLA-DR and CD71; enhanced expression of mRNAs for 13 different mediators of inflammation), and protein leakage (all p<0.05 vs. placebo/saline). Pretreatment with salmeterol inhibited LPS-induced neutrophil influx, neutrophil degranulation (myeloperoxidase), tumor necrosis factor alpha release, and HLA-DR expression (all p<0.05 vs. placebo/LPS), while not significantly influencing other responses. CONCLUSION Salmeterol exerts antiinflammatory effects in the pulmonary compartment of humans exposed to LPS.
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Affiliation(s)
- Nico A Maris
- Department of Experimental Internal Medicine, Academic Medical Center, University of Amsterdam, The Netherlands.
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35
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Thomas P, Hayashi H, Zimmer R, Forse RA. Regulation of cytokine production in carcinoembryonic antigen stimulated Kupffer cells by beta-2 adrenergic receptors: implications for hepatic metastasis. Cancer Lett 2004; 209:251-7. [PMID: 15159029 DOI: 10.1016/j.canlet.2003.12.027] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2003] [Revised: 12/19/2003] [Accepted: 12/19/2003] [Indexed: 12/15/2022]
Abstract
Elevated Carcinoembryonic antigen (CEA) levels in the serum indicate a poor prognosis for colorectal cancer patients. Induction of proinflammatory cytokines by CEA interaction with Kupffer cells has been proposed as a mechanism for hepatic metastasis formation. Studies show that the cytokine response in circulating and peritoneal macrophages is regulated by beta-adrenergic receptor signals, though little information is available regarding Kupffer cells. We investigated the relationship between beta-adrenergic receptor stimulation and the response of Kupffer cells to CEA. Comparisons between unstimulated and CEA stimulated rat Kupffer cells, using cDNA arrays, showed up-regulation (>4 fold) of the beta2-adrenergic receptor mRNA. Peak up-regulation occurred after 30 min with a decline at 1 h. We examined the effects of the specific beta2-adrenergic receptor agonist terbutaline on cytokine production by CEA stimulated rat Kupffer cells. Pre-treatment of Kupffer cells with terbutaline followed by CEA caused a significant increase in IL-6 and IL-10 production, but a significant reduction in TNF-alpha production (>3 fold). mRNA levels reflected those of the ELISA assays for IL-6 and IL-10 but not for TNF-alpha. For IL-6 and TNF-alpha, these changes were serum independent, while IL-10 was serum dependent. This response is different from LPS treated Kupffer cells where all three cytokines showed serum dependency. Overall, these data suggest that Kupffer cell stimulation by CEA is under beta-adrenergic receptor control and induction of the beta-receptor is an early event following CEA binding to its receptor. Control of TNF-alpha production is negatively affected by terbutaline, while that of IL-6 and IL-10 is positively controlled suggesting that very different beta-adrenergic receptor signaling pathways are involved.
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Affiliation(s)
- Peter Thomas
- Laboratory of Surgical Biology, Department of Surgery, Boston University School of Medicine, 801 Albany St, S310, Boston, MA 02118, USA.
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36
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Kostenis E. A glance at G-protein-coupled receptors for lipid mediators: a growing receptor family with remarkably diverse ligands. Pharmacol Ther 2004; 102:243-57. [PMID: 15246248 DOI: 10.1016/j.pharmthera.2004.04.005] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
A plethora of lipid-like molecules known to act as intracellular second messengers are now recognized to signal cells through plasma membrane 7 transmembrane G-protein-coupled receptors (GPCRs). This has been the result of a decade-long genetic hunt for novel sequences encoding 7 transmembrane receptor proteins and the efforts to pair novel sequences with biologically active substances of (partly) unknown molecular mechanism of action. Identification of novel GPCR ligand pairs represents the first step to shed more light into the mode of action of novel cellular signaling molecules in human health and disease and might represent a fruitful source for the development of new drugs, judged on the successful history of GPCR as drug targets. Since 2000, more than 16 reports became available on lipid mediators--as diverse as lysophospholipids, arachidonic acid metabolites, short-, medium-, and long-chain fatty acids as well as steroid-like molecules--exerting their effects as extracellular mediators via rhodopsin-like family GPCRs. These reports have opened new avenues for research in human lipid receptor physiology and pharmacology. Here, the current knowledge on the recently deorphanized lipid receptors, including their isolation, expression pattern, function, and possible physiological or pathological roles will be reviewed.
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Affiliation(s)
- Evi Kostenis
- 7TM Pharma A/S, 3 Fremtidsvej, 2970 Hoersholm, Denmark.
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Kawai K, Kuwahara K, Oizumi N, Kitagaki H, Fujisawa S. Effects of Carteolol Hydrochloride on theIn VitroProduction of LPS-Induced Proinflammatory Cytokines by Murine Macrophage. J Ocul Pharmacol Ther 2004; 20:237-45. [PMID: 15279728 DOI: 10.1089/1080768041223620] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
We investigated whether carteolol hydrochloride, which has intrinsic sympathomimetic activity (ISA), inhibits the production of proinflammatory cytokines using mouse macrophages (MPs) and peripheral-blood mononuclear cells (PBMCs). MPs and PBMCs were collected from BALB/C strain mice, treated simultaneously with lipopolysaccharide (LPS) and test agents (carteolol hydrochloride, timolol maleate, betaxolol hydrochloride, levobunolol hydrochloride, or nipradilol) in medium, and incubated in a CO2 incubator. TNF-alpha and IL-6 in medium were measured by ELISA. Carteolol hydrochloride significantly inhibited the production of TNF-alpha and IL-6 by MPs at 10(-5) M and higher (p < 0.01) or PBMCs at 10(-6) M and higher (p < 0.01) compared to the controls, while the other test agents had no inhibitory effect. Carteolol hydrochloride inhibited the production of proinflammatory cytokines by inflammatory cells, raising the possibility that this intraocular hypotensive drug may be expected to have anti-inflammatory effects in patients with increased intraocular tension and postoperative inflammation.
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Affiliation(s)
- Kenji Kawai
- Department of Ophthalmology, Tokai University, School of Medicine, Kanagawa, Japan
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Meltzer JC, MacNeil BJ, Sanders V, Pylypas S, Jansen AH, Greenberg AH, Nance DM. Contribution of the adrenal glands and splenic nerve to LPS-induced splenic cytokine production in the rat. Brain Behav Immun 2003; 17:482-97. [PMID: 14583240 DOI: 10.1016/s0889-1591(03)00084-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Both the hypothalamic pituitary adrenal axis (HPAA) and the sympathetic nervous system (SNS) can inhibit immune function and are regarded as the primary efferent pathways for neural-immune interactions. To determine if this relationship is maintained in vivo in response to an inflammatory stimulus, rats were injected intravenously (iv) with various doses of lipopolysaccharide (LPS) and splenic cytokine mRNA and protein levels were measured at several dose and time intervals post-injection. The spleen was chosen as the target organ because both the neural and hormonal inputs to the spleen can be selectively removed by splenic nerve cut (SNC) and adrenalectomy (ADX), respectively. Data from our dose response studies established that maximum levels of splenic cytokines were induced in response to relatively low doses of LPS. Minimal changes in LPS-induced splenic cytokine levels were observed in response to ADX, SNC, or a combination of the two procedures across several doses of LPS. These results suggest that there are aspects of immune regulation that are functionally removed from these central modulatory systems and that the counter-regulatory responses induced by LPS have minimal impact on the concurrent induction of cytokines by this inflammatory stimulus. The conceptual model of neural-immune regulation as an inhibitory feedback system, at least with regards to the early activational effects induced by an inflammatory stimulus, was not supported by these studies.
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Affiliation(s)
- Jonathan C Meltzer
- National Research Council of Canada Institute for Biodiagnostics, Winnipeg, MB, Canada R3B 1Y6
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Kawamata Y, Fujii R, Hosoya M, Harada M, Yoshida H, Miwa M, Fukusumi S, Habata Y, Itoh T, Shintani Y, Hinuma S, Fujisawa Y, Fujino M. A G protein-coupled receptor responsive to bile acids. J Biol Chem 2003; 278:9435-40. [PMID: 12524422 DOI: 10.1074/jbc.m209706200] [Citation(s) in RCA: 1214] [Impact Index Per Article: 55.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
So far some nuclear receptors for bile acids have been identified. However, no cell surface receptor for bile acids has yet been reported. We found that a novel G protein-coupled receptor, TGR5, is responsive to bile acids as a cell-surface receptor. Bile acids specifically induced receptor internalization, the activation of extracellular signal-regulated kinase mitogen-activated protein kinase, the increase of guanosine 5'-O-3-thio-triphosphate binding in membrane fractions, and intracellular cAMP production in Chinese hamster ovary cells expressing TGR5. Our quantitative analyses for TGR5 mRNA showed that it was abundantly expressed in monocytes/macrophages in human and rabbit. Treatment with bile acids was found to suppress the functions of rabbit alveolar macrophages including phagocytosis and lipopolysaccharide-stimulated cytokine productions. We prepared a monocytic cell line expressing TGR5 by transfecting a TGR5 cDNA into THP-1 cells that did not express TGR5 originally. Treatment with bile acids suppressed the cytokine productions in the THP-1 cells expressing TGR5, whereas it did not influence those in the original THP-1 cells, suggesting that TGR5 is implicated in the suppression of macrophage functions by bile acids.
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Affiliation(s)
- Yuji Kawamata
- Discovery Research Laboratories 1, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Wadai 10, Tsukuba, Ibaraki 300-4293, Japan
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Delgado M, Ganea D. Vasoactive intestinal peptide inhibits IL-8 production in human monocytes by downregulating nuclear factor kappaB-dependent transcriptional activity. Biochem Biophys Res Commun 2003; 302:275-83. [PMID: 12604342 DOI: 10.1016/s0006-291x(03)00149-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Although interleukin-8 (IL-8) is a chemokine that plays a beneficial and central role in the inflammatory response, hematopoiesis, and angiogenesis, excessive IL-8 production can be deleterious to the host, and its selective inhibition represents an important therapeutic goal. Vasoactive intestinal peptide (VIP) is a neuropeptide that acts as a potent anti-inflammatory agent inhibiting the function of activated macrophages/monocytes. The present study reports the effect of VIP on IL-8 production by stimulated human THP1 monocytes. VIP inhibits IL-8 production in a dose- and time-dependent manner at the mRNA level. VIP seems to act by inhibiting the NF-kappaB-dependent IL-8 gene activation. The specific VPAC1 receptor mediates the inhibitory effect of VIP. Two transduction pathways appear to be involved, a major cAMP-independent pathway that preferentially blocks nuclear translocation of NF-kappaB and its binding to the kappaB site of the IL-8 promoter, and a cAMP-dependent pathway that inhibits the activation and binding to the IL-8 promoter of both CREB-binding protein (CBP) and TATA box-binding protein (TBP), two transcriptional cofactors strictly required for the transactivating activity of NF-kappaB. These findings support the proposed role of VIP as a key endogenous anti-inflammatory agent and describe a novel mechanism, i.e., the inhibition of the production of monocyte-derived IL-8, and are of obvious physiological significance, because VIP, through the inhibition of IL-8 production, could reduce the monocyte-induced neutrophil chemotaxis/infiltration, an important event in the pathogenesis of several inflammatory and autoimmune disorders.
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Affiliation(s)
- Mario Delgado
- Department of Biological Sciences, Rutgers University, Newark, NJ 07102, USA.
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Feldman AM, Kadokami T, Higuichi Y, Ramani R, McTiernan CF. The role of anticytokine therapy in heart failure: recent lessons from preclinical and clinical trials? Med Clin North Am 2003; 87:419-40. [PMID: 12693732 DOI: 10.1016/s0025-7125(02)00189-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
In summary, over a decade of investigation has demonstrated the pathophysiologic importance of TNF in the development and progression of cardiac dilatation and heart failure. Although the signaling pathways that regulate the cardiac production of TNF have not yet been identified and the potential benefits of TNF expression to the heart are not understood, the benefits of anticytokine therapy in animal models is marked. Unfortunately, these salutary effects in the laboratory have not transitioned to the bedside. To accomplish the translational portion of the cytokine story, we must identify the point in time during the transition from compensated to decompensated heart failure in which TNF is expressed. In addition, we must better understand the role that other down-stream and non-TNF-dependent cytokines play in the development of heart failure. Not all patients are the same; therefore, we must pursue clinical trials that will allow us to elucidate the optimal degree of TNF inhibition, identify the patients who are most likely to respond to TNF inhibition, and determine what the true, long-term effects of TNF inhibition may be. Finally, we must recognize that inflammatory activities can exist in tissues and organs in the absence of TNF. Thus, anticytokine strategies alone might not be effective in ameliorating the signs and symptoms of heart failure. It is hoped that the failure of recent studies to demonstrate salutary benefits in patients with class II to IV heart failure will not diminish enthusiasm for the long-term potential of anticytokine therapy.
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Affiliation(s)
- Arthur M Feldman
- Department of Medicine, Thomas Jefferson University Medical College, Philadelphia, PA 19107, USA.
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Delgado M, Ganea D. Vasoactive intestinal peptide inhibits IL-8 production in human monocytes. Biochem Biophys Res Commun 2003; 301:825-32. [PMID: 12589787 DOI: 10.1016/s0006-291x(03)00059-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Vasoactive intestinal peptide (VIP), a neuropeptide present in the lymphoid microenvironment, acts as a potent anti-inflammatory agent that inhibits the function of activated macrophages. VIP was shown to inhibit IL-6, TNFalpha, IL-12, chemokine, and nitric oxide production in endotoxin-activated macrophages. The present study reports the effect of VIP on IL-8 production by stimulated human monocytes. VIP inhibits IL-8 production in a dose- and time-dependent manner at the mRNA level. The specific VPAC1 receptor mediates the inhibitory effect of VIP. Two transduction pathways appear to be involved, a major cAMP-independent pathway and a secondary cAMP-dependent pathway. Of obvious physiological significance is the fact that VIP, presumably through the inhibition of IL-8 production, dramatically reduces the monocyte-induced neutrophil chemotaxis, an important event in the pathogenesis of several inflammatory and autoimmune disorders. These findings support the proposed role of VIP as a key endogenous anti-inflammatory agent and describe a novel mechanism, i.e., the inhibition of the production of monocyte-derived IL-8.
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Affiliation(s)
- Mario Delgado
- Department of Biological Sciences, Rutgers University, Newark, NJ 07102, USA.
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Hamano H, Noguchi M, Fukui H, Issiki A, Watanabe Y. Regulation of brain cell environment on neuronal protection: role of TNFalpha in glia cells. Life Sci 2002; 72:565-74. [PMID: 12467897 DOI: 10.1016/s0024-3205(02)02252-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Bacterial endotoxin lipopolysaccharide (LPS) treatment of neuron-rich cells and glia-rich cells exhibited significant cell damage 12 hr after incubation, although no severe or significant cell damage induced by LPS appeared in neuron-glia co-cultured cells. Moreover, severe and significant time-dependent cell damage was induced by a larger dose treatment (10 mM) of glutamate (Glu), and this damage was seen in neuron-rich cells, neuron-glia co-cultured cells, and glia-rich cells. Examining extracellular tumor necrosis factor alpha (TNFalpha) induced by either LPS or Glu treatment, the levels of extracellular TNFalpha induced by LPS were significantly higher than those induced by Glu. These significant increases of TNFalpha were measured within 2 hr after LPS treatment in neuron-glia co-cultured cells and glia-rich cells, although no significant changes were detected in the neuron-rich cells. With Glu treatment, a significant increase in TNFalpha levels was detected after 6 hr of Glu treatment only in glia-rich cells. Our results indicate that cerebral TNFalpha is mainly produced in glia cells and that its production is dependently regulated by each stimulant. In addition, the production of TNFalpha is not directly related to the trigger of cell injury.
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Affiliation(s)
- Hiroko Hamano
- Department of Anesthesiology, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, 160-0023, Tokyo, Japan
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Castellani JW, M Brenner IK, Rhind SG. Cold exposure: human immune responses and intracellular cytokine expression. Med Sci Sports Exerc 2002; 34:2013-20. [PMID: 12471310 DOI: 10.1097/00005768-200212000-00023] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
It is commonly believed that exposure to cold environmental temperatures depresses immune function and increases the risk for infection. This review paper will 1) present an overview of human physiological responses to cold exposure, 2) present the human studies examining the effects of cold exposure on immune responses, and 3) summarize recent experiments from our laboratories examining the effects of exercise and fatigue on immune responses during subsequent cold exposure. Based on the review of the literature, there is no support for the concept that cold exposure depresses immune function.
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Affiliation(s)
- John W Castellani
- USARIEM, Thermal and Mountain Medicine Division, 42 Kansas Street, Natick, MA 01760-5007, USA.
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45
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Van Miert ASJPAM. Present concepts on the inflammatory modulators with special reference to cytokines. Vet Res Commun 2002; 26:111-26. [PMID: 11924601 DOI: 10.1023/a:1014043601287] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The pro- and anti-inflammatory cytokines create a network of interactions between cells that lead to both stimulatory and inhibitory responses that maintain an effective homeostatic regulation. The anti-inflammatory cytokines are a family of peptides that modulate the pro-inflammatory cytokine response. Cytokines act in concert with non-cytokine mediators, such as prostaglandin E2, glucocorticosteroids, lipocortins, and catecholamines. This review highlights new developments in our understanding of the pathophysiology of inflammation and gives an example of a more recent approach to the modulation of acute systemic inflammatory disorders; activation of beta2-adrenergic receptors on macrophages. In this respect the potent beta2-adrenergic agonist clenbuterol seems of therapeutic interest.
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Affiliation(s)
- A S J P A M Van Miert
- Department of Veterinary Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, Utrecht University , The Netherlands
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46
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Fujisawa T, Kato Y, Terada A, Iguchi K, Kamiya H. Synergistic effect of theophylline and procaterol on interleukin-5-induced degranulation from human eosinophils. J Asthma 2002; 39:21-7. [PMID: 11883736 DOI: 10.1081/jas-120000803] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Inhibiting the release of toxic granule proteins from eosinophils is a possible means of treating allergic inflammation. This study was performed to examine whether procaterol and theophylline, commonly used bronchodilators in asthma, inhibit eosinophil degranulation induced by interleukin (IL)-5. Purified eosinophils from patients with asthma were incubated with IL-5 for 24 hr in the presence of theophylline, procaterol, combinations of theophylline and procaterol, or dexamethasone. Levels of eosinophil-derived neurotoxin (EDN) in the supernatants were measured with radioimmunoassay. Theophylline inhibited IL-5-induced release of EDN in a concentration-dependent manner. Procaterol inhibited degranulation only at high concentrations. However, procaterol at 10(-9) M and 10(-8) M, which are physiologic concentrations, together with theophylline at 10(-5) M, which is a concentration commonly found in the serum of patients receiving low-dose theophylline, inhibited degranulation by 43.8%. This finding indicates that theophylline and procaterol have synergistic effects. The inhibition was comparable to that with dexamethasone at 10(-9) M. Our results suggest that a combination of low-dose theophylline and procaterol exhibits antiinflammatory effects in asthma by inhibiting eosinophil-effector functions.
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Affiliation(s)
- Takao Fujisawa
- Department of Pediatrics and Allergy, National Mie Hospital, Tsu City, Japan.
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47
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Retter AS, Frishman WH. The role of tumor necrosis factor in cardiac disease. HEART DISEASE (HAGERSTOWN, MD.) 2001; 3:319-25. [PMID: 11975813 DOI: 10.1097/00132580-200109000-00008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Tumor necrosis factor (TNF) is a proinflammatory cytokine that can produce widespread deleterious effects when expressed in large amounts. It is produced in the heart by both cardiac myocytes and resident macrophages under conditions of cardiac stress, and is thought to be responsible for many of the untoward manifestations of cardiac disease. This article discusses the role of TNF in heart disease and some potential therapeutic modalities that can influence the cytokine activity. The results of controlled studies would suggest that TNF inhibition does not influence the clinical course of patients with heart failure.
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Affiliation(s)
- A S Retter
- Department of Internal Medicine, Temple University Hospital, Philadelphia, Pennsylvania 19004, USA
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48
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Rhind SG, Castellani JW, Brenner IK, Shephard RJ, Zamecnik J, Montain SJ, Young AJ, Shek PN. Intracellular monocyte and serum cytokine expression is modulated by exhausting exercise and cold exposure. Am J Physiol Regul Integr Comp Physiol 2001; 281:R66-75. [PMID: 11404280 DOI: 10.1152/ajpregu.2001.281.1.r66] [Citation(s) in RCA: 78] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
This study tested the hypothesis that exercise elicits monocytic cytokine expression and that prolonged cold exposure modulates such responses. Nine men (age, 24.6 +/- 3.8 y; VO(2 peak), 56.8 +/- 5.6 ml. kg(-1). min(-1)) completed 7 days of exhausting exercise (aerobic, anaerobic, resistive) and underwent three cold, wet exposures (CW). CW trials comprised </=6 h (six 1-h rest-work cycles) exposure to cold (5 degrees C, 20 km/h wind) and wet (5 cm/h rain) conditions. Blood samples for the determination of intracellular and serum cytokine levels and circulating hormone concentrations were drawn at rest (0700), after exercise (approximately 1130), and after CW (~2000). Whole blood was incubated with (stimulated) or without (spontaneous) lipopolysaccharide (LPS; 1 microgram/ml) and stained for CD14 monocyte surface antigens. Cell suspensions were stained for intracellular cytokine expression and analyzed by flow cytometry. The proportion of CD14(+) monocytes exhibiting spontaneous and stimulated intracellular expression of interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha increased after exercise, but these cells produced less IL-1beta and TNF-alpha after CW when CW was preceded by exhausting exercise. Serum cytokine concentrations followed a parallel trend. These findings suggest that blood monocytes contribute to exercise-induced cytokinemia and that cold exposure can differentially modulate cytokine production, upregulating expression of IL-6 and IL-1 receptor antagonist but downregulating IL-1beta and TNF-alpha. The cold-induced changes in cytokine expression appear to be linked to enhanced catecholamine secretion associated with cold exposure.
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Affiliation(s)
- S G Rhind
- Defence and Civil Institute of Environmental Medicine, Toronto, M3M 3B9, Ontario M5S 1A1 Canada
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49
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Kast RE. Tumor necrosis factor has positive and negative self regulatory feed back cycles centered around cAMP. INTERNATIONAL JOURNAL OF IMMUNOPHARMACOLOGY 2000; 22:1001-6. [PMID: 11090708 DOI: 10.1016/s0192-0561(00)00046-1] [Citation(s) in RCA: 48] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
This paper reviews data that allow recognition of, (1) two opposing intracellular chains of events occurring subsequent to an increase in tumor necrosis factor, TNF, and (2) that these two chains have opposing effects on intracellular cyclic adenosine monophosphate, cAMP. The two chains - attenuation cycle, where TNF results in prostaglandin E mediated increased cAMP and, consequent to this, suppression of TNF levels; and an amplification cycle, where increased TNF increases intracellular cyclic adenosine phosphodiesterase, lowering cAMP, thereby raising TNF levels further. TNF is a central mediator in several inflammatory diseases. Understanding TNF control systems will allow better delineation of pathophysiology and clinical care.
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50
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Abstract
Evidence of dystrophic muscle degeneration in the hind limb muscles of young (20-week-old) treadmill-exercised or aged (87-week-old) sedentary mdx mice was greatly reduced by treatment with clenbuterol, a beta(2)-adrenoceptor agonist. Daily treadmill exercise for 10 weeks increased the size of regions within the mdx plantaris but not the soleus or gastrocnemius muscles, in which necrotic muscle fibers or the absence of fibers was observed. Clenbuterol reduced the size of these abnormal regions from 21% of total muscle cross-sectional area to levels (4%) found in sedentary mdx mice. In addition, the muscles obtained from aged clenbuterol-treated mdx or wild-type mice did not display the extensive fibrosis or fiber loss observed in untreated mdx mice. These observations are consistent with a mechanism of dystrophic muscle degeneration caused by work load-induced injury that is cumulative with aging and is opposed by beta(2)-adrenoceptor activation. Optimization of beta(2)-agonist treatment of muscular dystrophy in mdx mice may lead to a useful therapeutic modality for human forms of the disease.
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MESH Headings
- Adrenergic beta-Agonists/pharmacology
- Aging/physiology
- Animals
- Clenbuterol/pharmacology
- Humans
- Mice
- Mice, Inbred C57BL
- Mice, Inbred mdx
- Muscle Development
- Muscle, Skeletal/drug effects
- Muscle, Skeletal/growth & development
- Muscle, Skeletal/pathology
- Muscle, Skeletal/physiopathology
- Muscular Dystrophy, Animal/pathology
- Muscular Dystrophy, Animal/physiopathology
- Muscular Dystrophy, Animal/prevention & control
- Physical Conditioning, Animal/physiology
- Physical Exertion/drug effects
- Physical Exertion/physiology
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Affiliation(s)
- R J Zeman
- Department of Cell Biology and Anatomy, New York Medical College, Valhalla, New York 10595, USA.
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