Suppression of TNF-α and IL-1 signaling identifies a mechanism of homeostatic regulation of macrophages by IL-27.
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.
Kalliolias
George D
GD
Arthritis and Tissue Degeneration Program, Department of Medicine, Hospital for Special Surgery, New York, NY 10021, USA.
Gordon
Rachael A
RA
Ivashkiv
Lionel B
LB
D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002908:Chronic Disease; D015536:Down-Regulation / Q000276:immunology; D006706:Homeostasis / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors* / Q000502:physiology*; D007378:Interleukins / Q000096:biosynthesis / Q000502:physiology*; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000276:immunology*; D013582:Synovial Fluid / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000502:physiology*
D018836:Inflammation Mediators; D053583:Interleukin-1beta; D007378:Interleukins; C464565:MYDGF protein, human; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha