Lipopolysaccharide-mediated IL-10 transcriptional regulation requires sequential induction of type I IFNs and IL-27 in macrophages.
IL-10 is a potent anti-inflammatory molecule that regulates excessive production of inflammatory cytokines during an infection or tissue damage. Dysregulation of IL-10 is associated with a number of autoimmune diseases, and so, understanding the mechanisms by which IL-10 gene expression is regulated remains an important area of study. Macrophages represent a major source of IL-10, which is generated in response to TLR signaling as a feedback mechanism to curtail inflammatory response. In this study, we identify a signaling pathway in murine bone marrow-derived macrophages in which activation of TLR4 by LPS induces the expression of IL-10 through the sequential induction of type I IFNs followed by induction and signaling through IL-27. We demonstrate that IL-27 signaling is required for robust IL-10 induction by LPS and type I IFNs. IL-27 leads directly to transcription of IL-10 through the activation of two required transcription factors, STAT1 and STAT3, which are recruited to the IL-10 promoter. Finally, through systematic functional promoter-reporter analysis, we identify three cis elements within the proximal IL-10 promoter that play an important role in regulating transcription of IL-10 in response to IL-27.
Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Shankar Subramanian
SS
Iyer
Amir Ali
AA
Ghaffari
Genhong
G
Cheng
D000818:Animals; D019898:Autocrine Communication / Q000235:genetics / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D007370:Interferon Type I / Q000096:biosynthesis* / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism; D007378:Interleukins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019899:Paracrine Communication / Q000235:genetics / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D014158:Transcription, Genetic / Q000276:immunology*; D015533:Transcriptional Activation / Q000276:immunology*
C486767:Il27 protein, mouse; D007370:Interferon Type I; D007378:Interleukins; D008070:Lipopolysaccharides; D016753:Interleukin-10