IL-6 trans signalling drives a STAT3 dependant pathway that leads to hyperactive TGF-{beta} signalling promoting SMAD3 activation and fibrosis via gremlin [Cell Biology]

February 18th, 2014 by O'Reilly, S., Ciechomska, M., Cant, R., van Laar, J. M.

Fibrosis is a common and intractable condition associated with various pathologies. It is characterised 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 analysed the signalling pathways that underscore the IL-6 mediated induction of collagen. We show that IL-6 trans signalling is important and that the effect is dependent on STAT3, however the effect is indirect and mediated through enhanced TGF-β signalling and the classic downstream cellular mediator Smad3. This is due to induction of the BMP antagonist Gremlin-1 and we show that Gremlin-1 is pro-fibrotic and is mediated through canonical TGF-β signalling.
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