| Suppression of TNF-α and IL-1 signaling identifies a mechanism of homeostatic regulation of macrophages by IL-27. | |
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MedLine Citation:
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PMID: 20971923 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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IL-27 is a pleiotropic cytokine with both activating and inhibitory functions on innate and acquired immunity. IL-27 is expressed at sites of inflammation in cytokine-driven autoimmune/inflammatory diseases, such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, and sarcoidosis. However, its role in modulating disease pathogenesis is still unknown. In this study, we found that IL-27 production is induced by TNF-α in human macrophages (MΦ) and investigated the effects of IL-27 on the responses of primary human MΦ to the endogenous inflammatory cytokines TNF-α and IL-1. In striking contrast to IL-27-mediated augmentation of TLR-induced cytokine production, we found that IL-27 suppressed MΦ responses to TNF-α and IL-1β, thus identifying an anti-inflammatory function of IL-27. IL-27 blocked the proximal steps of TNF-α signaling by downregulating cell-surface expression of the signaling receptors p55 and p75. The mechanism of inhibition of IL-1 signaling was downregulation of the ligand-binding IL-1RI concomitant with increased expression of the receptor antagonist IL-1Ra and the decoy receptor IL-1RII. These findings provide a mechanism for suppressive effects of IL-27 on innate immune cells and suggest that IL-27 regulates inflammation by limiting activation of MΦ by inflammatory cytokines while preserving initial steps in host defense by augmenting responses to microbial products. |
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Authors:
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George D Kalliolias; Rachael A Gordon; Lionel B Ivashkiv |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-10-22 |
Journal Detail:
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Title: Journal of immunology (Baltimore, Md. : 1950) Volume: 185 ISSN: 1550-6606 ISO Abbreviation: J. Immunol. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-11-18 Completed Date: 2011-01-10 Revised Date: 2012-05-10 |
Medline Journal Info:
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Nlm Unique ID: 2985117R Medline TA: J Immunol Country: United States |
Other Details:
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Languages: eng Pagination: 7047-56 Citation Subset: AIM; IM |
Affiliation:
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Arthritis and Tissue Degeneration Program, Department of Medicine, Hospital for Special Surgery, New York, NY 10021, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Arthritis, Rheumatoid
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immunology,
metabolism,
pathology Cells, Cultured Chronic Disease Down-Regulation / immunology Homeostasis / immunology* Humans Immunity, Innate Inflammation Mediators / antagonists & inhibitors, metabolism, physiology Interleukin-1beta / antagonists & inhibitors*, physiology* Interleukins / biosynthesis, physiology* Macrophage Activation / immunology Macrophages / immunology*, metabolism, pathology Receptors, Tumor Necrosis Factor, Type II / antagonists & inhibitors Signal Transduction / immunology* Synovial Fluid / immunology, metabolism Tumor Necrosis Factor-alpha / antagonists & inhibitors*, physiology* |
| Grant Support | |
ID/Acronym/Agency:
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R01 AI044938-10/AI/NIAID NIH HHS; R01 AI044938-11/AI/NIAID NIH HHS; R01 AI044938-12/AI/NIAID NIH HHS; R01 AI044938-13/AI/NIAID NIH HHS; R01 AI046712-12/AI/NIAID NIH HHS; R01 AI046712-13/AI/NIAID NIH HHS; R01 AR046713-12/AR/NIAMS NIH HHS; R01 AR046713-13/AR/NIAMS NIH HHS; R01 AR050401/AR/NIAMS NIH HHS; R01 AR050401-05/AR/NIAMS NIH HHS; R01 AR050401-06A2/AR/NIAMS NIH HHS; R01 DE019420-02/DE/NIDCR NIH HHS; R01 DE019420-03/DE/NIDCR NIH HHS; R01 DE019420-04/DE/NIDCR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/IL27 protein, human; 0/Inflammation Mediators; 0/Interleukin-1beta; 0/Interleukins; 0/Receptors, Tumor Necrosis Factor, Type II; 0/Tumor Necrosis Factor-alpha |
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