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

O'Reilly, Steven, Ciechomska, Marzena, Cant, Rachel and van Laar, Jacob M. (2014) Interleukin-6 (IL-6) Trans Signaling Drives a STAT3-dependent Pathway That Leads to Hyperactive Transforming Growth Factor-β (TGF-β) Signaling Promoting SMAD3 Activation and Fibrosis via Gremlin Protein. Journal of Biological Chemistry, 289 (14). pp. 9952-9960. ISSN 0021-9258

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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.

Item Type:	Article
Uncontrolled Keywords:	Cell Biology, Collagen, Fibrogenesis, Interleukin, Signal Transduction, Interleukin-6, Extracellular
Subjects:	C400 Genetics
Department:	Faculties > Health and Life Sciences > Applied Sciences
Depositing User:	Ellen Cole
Date Deposited:	11 Oct 2018 12:30
Last Modified:	10 Oct 2019 15:15
URI:	http://nrl.northumbria.ac.uk/id/eprint/35238

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