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.
Arthritis and Tissue Degeneration Program, Department of Medicine, Hospital for Special Surgery, New York, NY 10021, USA.
George D
GD
Kalliolias
Rachael A
RA
Gordon
Lionel B
LB
Ivashkiv
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