Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 289, Issue 14, Pages 9952-9960Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.545822
Keywords
Cell Biology; Collagen; Fibrogenesis; Interleukin; Signal Transduction; Interleukin-6; Extracellular
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Background: IL-6 is a profibrotic molecule, but the mechanism is unclear. Results: IL-6 mediates fibrosis via a STAT3- and Smad3-dependent pathway mediated via a novel cytokine, Gremlin. Conclusion: A novel pathway of IL-6 mediated fibrogenesis has been defined. Significance: Targeting Gremlin is a new therapeutic target in fibrosis downstream of STAT3. Fibrosis is a common and intractable condition associated with various pathologies. It is characterized by accumulation of an excessive amount of extracellular matrix molecules that primarily include collagen type I. IL-6 is a profibrotic cytokine that is elevated in the prototypic fibrotic autoimmune condition systemic sclerosis and is known to induce collagen I expression, but the mechanism(s) behind this induction are currently unknown. Using healthy dermal fibroblasts in vitro, we analyzed the signaling pathways that underscore the IL-6-mediated induction of collagen. We show that IL-6 trans signaling is important and that the effect is dependent on STAT3; however, the effect is indirect and mediated through enhanced TGF- signaling and the classic downstream cellular mediator Smad3. This is due to induction of the bone morphogenetic protein (BMP) antagonist Gremlin-1, and we show that Gremlin-1 is profibrotic and is mediated through canonical TGF- signaling.
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