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Interleukin-6 (IL-6) Trans Signaling Drives a STAT3-dependent Pathway That Leads to Hyperactive Transforming Growth Factor-beta (TGF-beta) Signaling Promoting SMAD3 Activation and Fibrosis via Gremlin Protein

Lookup NU author(s): Dr Steven O'Reilly, Dr Marzena Ciechomska, Rachel Cant, Professor Jaap van Laar

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Abstract

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.

Publication metadata

Author(s): O'Reilly S, Ciechomska M, Cant R, van Laar JM

Publication type: Article

Publication status: Published

Journal: Journal of Biological Chemistry

Year: 2014

Volume: 289

Issue: 14

Pages: 9952-9960

Print publication date: 04/04/2014

Online publication date: 18/02/2014

ISSN (print): 0021-9258

ISSN (electronic): 1083-351X

Publisher: American Society for Biochemistry and Molecular Biology, Inc.

URL: http://dx.doi.org/10.1074/jbc.M113.545822

DOI: 10.1074/jbc.M113.545822

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