The IL-6 Trans-Signaling-STAT3 Pathway Mediates ECM and Cellular Proliferation in Fibroblasts from Hypertrophic Scar

Abstract

The molecular mechanisms behind the pathogenesis of post-burn hypertrophic scar (HS) remain unclear. Here, we investigate the role of interleukin-6 (IL-6) trans-signaling-STAT3 pathway in HS fibroblasts (HSF) derived from burned-induced HS skin. HSF showed increased Tyr 705 STAT3 phosphorylation over normal fibroblast (NF) after IL-6•IL-6Rα stimulation by immunoassays. The endogenous STAT3 target gene, SOCS3, was upregulated in HSF and showed increased STAT3 binding on its promoter relative to NF in Chromatin Immunoprecipitation assay. We observed that the cell surface signaling transducer glycoprotein 130 is upregulated in HSF using Q-RT-PCR and flow cytometry. The production of excessive extracellular matrix (ECM), including the expression of alpha2 (1) procollagen (Col1A2) and fibronectin 1 (FN) were seen in HSFs. A STAT3 peptide inhibitor abrogated FN and Col1A2 gene expression in HSF indicating involvement of STAT3 in ECM production. The cellular proliferation markers Cyclin D1, Bcl-Xl and c-Myc were also upregulated in HSF and knockdown of STAT3 by siRNA attenuated c-Myc expression indicating the essential role of STAT3 in fibroblast proliferation. Taken together, our results suggest that the IL-6-trans-signaling-STAT3 pathway may play an integral role in HS pathogenesis and disruption of this pathway could be a potential therapeutic strategy for the treatment of burn-induced HS.