A3.22 IL-6 trans signalling drives collagen via an epigenetic mechanism mediated through SMAD3. (31st January 2014)

• Record Type: Journal Article
• Authors: O'Reilly, Steven; Chiechomska, Marzena; van Laar, Jacob M
• Is Part Of: Annals of the rheumatic diseases. Volume 73:Supplement 1(2014)
• Page Start: A50
• Page End: A51
• Publication Date: 2014-01-31
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2013-205124.115
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: Systemic sclerosis is an autoimmune condition of unknown aetiology. The disease consists of autoimmunity, vascular disease, inflammation and ultimately fibrosis. 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 autoimmune condition systemic sclerosis and is known to induce collagen I expression but the mechanism (s) behind this induction are currently unknown. Methods: Dermal fibroblasts were isolated from biopsies from healthy donors and SSc patients and treated with IL-6&sIL-6R in vitro in serum free media. Collagen was analysed using qRT-PCR and siRNA was employed for STAT3 and SMAD3 silencing. MicroRNA was analysed using specific primers and normalised to SNORD. Results: 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 Signal Transducer and Activator of Transcription 3 (STAT3), however the effect is indirect and mediated through enhanced TGF-β signalling and the classic downstream mediator Smad3 as silencing abrogated the effect. This induces collagen expression through the repression of the expression of the fibrotic microRNA (miR) 29a as collagen I is its bona fide target gene. Transfection of miR29a mimics reverses the diseased collagen overexpression in SSc fibroblasts. Conclusion: IL-6 is driving the fibrosis through STAT3 and SMAD-mediated mechanisms that repress miR29a and thus upregulate collagen. Strategies that block IL-6 signalling will cause derepression of miR29a and normalisation of collagen levels.