title: 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 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.
authors.affiliation: Department of Internal Medicine, Endocrinology Division, University of Texas Medical Branch, Galveston, Texas 77555-1060, USA. suray@utmb.edu
authors.forename: Sutapa
authors.initials: S
authors.lastname: Ray
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Ju
authors.forename: Hong
authors.initials: H
authors.lastname: Sun
authors.forename: Celeste C
authors.initials: CC
authors.lastname: Finnerty
authors.forename: David N
authors.initials: DN
authors.lastname: Herndon
authors.forename: Allan R
authors.initials: AR
authors.lastname: Brasier
mesh_terms: D049109:Cell Proliferation; D017439:Cicatrix, Hypertrophic / Q000378:metabolism / Q000473:pathology*; D024042:Collagen Type I / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D005109:Extracellular Matrix / Q000502:physiology*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D005353:Fibronectins / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D015854:Up-Regulation; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D005353:Fibronectins; D006023:Glycoproteins; D015850:Interleukin-6; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D050796:STAT3 Transcription Factor; D051020:bcl-X Protein; C480482:glycoprotein 130, human; D019938:Cyclin D1