Lipopolysaccharide-mediated IL-10 transcriptional regulation requires sequential induction of type I IFNs and IL-27 in macrophages

• Published in: The Journal of immunology (1950) Vol. 185; no. 11; pp. 6599 - 6607
• Main Authors: Iyer, Shankar Subramanian, Ghaffari, Amir Ali, Cheng, Genhong
• Format: Journal Article
• Language: English
• Published: United States 01.12.2010
• Subjects: Animals; Autocrine Communication - genetics; Autocrine Communication - immunology; Bone Marrow Cells - immunology; Bone Marrow Cells - metabolism; Cell Line; Interferon Type I - biosynthesis; Interferon Type I - genetics; Interleukin-10 - genetics; Interleukin-10 - metabolism; Interleukins - biosynthesis; Interleukins - genetics; Interleukins - physiology; Lipopolysaccharides - pharmacology; Macrophages - immunology; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Paracrine Communication - genetics; Paracrine Communication - immunology; Promoter Regions, Genetic - immunology; Signal Transduction - genetics; Signal Transduction - immunology; Transcription, Genetic - immunology; Transcriptional Activation - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1002041

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.