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

• Published in: Journal of investigative dermatology Vol. 133; no. 5; pp. 1212 - 1220
• Main Authors: Ray, Sutapa, Ju, Xiaoxi, Sun, Hong, Finnerty, Celeste C., Herndon, David N., Brasier, Allan R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2013; Elsevier Limited
• Subjects: bcl-X Protein - metabolism; Cell Proliferation; Cicatrix, Hypertrophic - metabolism; Cicatrix, Hypertrophic - pathology; Collagen Type I - metabolism; Cyclin D1 - metabolism; Extracellular Matrix - physiology; Fibroblasts - metabolism; Fibroblasts - pathology; Fibronectins - metabolism; Glycoproteins - metabolism; Humans; Interleukin-6 - physiology; Proto-Oncogene Proteins c-myc - metabolism; Signal Transduction - physiology; STAT3 Transcription Factor - physiology; Up-Regulation
• ISSN: 0022-202X; 1523-1747
• DOI: 10.1038/jid.2012.499

The molecular mechanisms behind the pathogenesis of postburn hypertrophic scar (HS) remain unclear. Here, we investigate the role of the IL-6 trans-signaling-signal transducer and activator of transcription (STAT)3 pathway in HS fibroblasts (HSFs) derived from post-burn HS skin. HSF showed increased Tyr 705 STAT3 phosphorylation compared with normal fibroblast (NF) after IL-6•IL-6Rα stimulation by immunoassays. The endogenous STAT3 target gene, SOCS3, was upregulated in HSFs and showed increased STAT3 binding on its promoter relative to NFs in a chromatin immunoprecipitation assay. We observed that the cell-surface signaling transducer glycoprotein 130 is upregulated in HSFs by quantitative real-time reverse-transcriptase–PCR and flow cytometry. The production of excessive extracellular matrix (ECM), including the expression of alpha2 (1) procollagen (Col1A2) and fibronectin 1 (FN), was seen in HSFs. A STAT3 peptide inhibitor abrogated FN and Col1A2 gene expression in HSFs 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 small interfering RNA 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 have an integral role in HS pathogenesis, and disruption of this pathway could be a potential therapeutic strategy for the treatment of post-burn HS.