Abstract
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-β 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-β signaling.
Highlights
IL-6 is a profibrotic molecule, but the mechanism is unclear
SSc dermal fibroblasts cultured from lesional skin of patients have elevated phosphorylated STAT3, which stays elevated in culture [17], and blockade of JAK2, which lies upstream of STAT3, reduced collagen levels in these cells and in the bleomycin model of fibrosis [17], suggesting that Janus kinases (JAKs) play a critical role in fibrosis
JAKs and signal transducers and activators of transcription (STATs) Drive IL-6-induced Collagen Expression— We and others had previously demonstrated that incubation with IL-6 and sIL-6R leads to Collagen1A1 expression in APRIL 4, 2014
Summary
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. Receptor-associated Janus kinases (JAKs) are activated, and signal transducers and activators of transcription (STATs) transcription factors are phosphorylated and translocate to the cell nucleus to coordinate gene expression by binding to STAT-responsive gene elements [12, 13]. These JAKs do not possess tyrosine kinase activity themselves. SSc dermal fibroblasts cultured from lesional skin of patients have elevated phosphorylated STAT3, which stays elevated in culture [17], and blockade of JAK2, which lies upstream of STAT3, reduced collagen levels in these cells and in the bleomycin model of fibrosis [17], suggesting that JAKs play a critical role in fibrosis. To gain an understanding of the underlying molecular mechanism of IL-6 trans signaling in fibrosis, we used dermal fibroblasts to examine the role of the downstream signaling pathways utilized that lead to fibrosis
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