IL-27 activates human monocytes via STAT1 and suppresses IL-10 production but the inflammatory functions of IL-27 are abrogated by TLRs and p38.
IL-27 is a member of the IL-12 family of cytokines that activates the Jak-STAT signaling pathway in a context-dependent manner and has pleiotropic effects on acquired immunity. IL-27 has the capacity to promote early stages of Th1 generation, but recent evidence has suggested a predominant suppressive effect on Th1, Th2, and Th17 differentiation. Although modest suppressive effects of IL-27 on myeloid lineage cells have been observed, there is limited knowledge about the role of IL-27 in the regulation of innate immunity. In this study we report that although in resting murine macrophages IL-27 had minimal if any effects, in resting human monocytes IL-27 had profound proinflammatory functions. IL-27 activated a STAT1-dominant pattern of signaling in human monocytes with the consequent activation of STAT1-dependent inflammatory target genes. IL-27 primed monocytes for augmented responses to TLR stimulation in a STAT1-dependent manner, altered IL-10 signaling, and attenuated IL-10-induced gene expression. Strikingly, IL-27 strongly suppressed TLR-induced IL-10 production in human monocytes. However, the proinflammatory effects of IL-27 on human monocytes were rapidly abrogated by LPS via a p38-mediated mechanism that inhibited IL-27 signaling. Our findings identify a predominantly proinflammatory function for IL-27 in human monocytes and suggest a mechanism by which the activating effects of IL-27 on innate immunity are attenuated as an immune response proceeds and IL-27 transitions to predominantly suppressive effects on acquired immunity.
Kalliolias
George D
GD
Arthritis and Tissue Degeneration Program, Department of Medicine, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021, USA.
Ivashkiv
Lionel B
LB
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D016753:Interleukin-10 / Q000276:immunology*; D007378:Interleukins / Q000276:immunology*; D053612:Janus Kinases / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000276:immunology; D051379:Mice; D009000:Monocytes / Q000276:immunology*; D050794:STAT1 Transcription Factor / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology*
C508609:IL10 protein, human; C486767:Il27 protein, mouse; D007378:Interleukins; D008070:Lipopolysaccharides; C464565:MYDGF protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D051193:Toll-Like Receptors; D016753:Interleukin-10; D053612:Janus Kinases; D048051:p38 Mitogen-Activated Protein Kinases