title: Control of IL-6 expression and response in fibroblasts from patients with systemic sclerosis.
abstract: Systemic sclerosis (SSc) is an autoimmune connective tissue disease of unknown etiology in which aberrant fibroblast function results in fibrosis of the skin and internal organs. A distinguishing feature of dermal fibroblasts cultured from SSc lesions is that they produce constitutively, i.e., without exogenous stimulation, as much as 30-fold more interleukin-6 (IL-6) than do normal fibroblasts. The present study indicates that the mechanism of constitutive IL-6 secretion involves the accumulation of IL-6 mRNA in affected SSc fibroblasts, mediated by the constitutive binding of nuclear factors to the IL-6 promoter. DNA-protein complexes formed using nuclear extracts of constitutively expressing cells are distinct from those using extracts of normal cells, with or without exogenous stimulation of IL-6; thus, the mechanisms which regulate constitutive and inducible IL-6 gene expression are apparently distinct. The data also demonstrate that dermal fibroblasts respond very rapidly to IL-6 by increasing expression of the IL-6 gene, thus suggesting a mechanism for the establishment and/or persistence of constitutive expression. The constitutive secretion of IL-6 may play an important role in the perpetuation of the local immune dysregulation and fibroblast activation in the SSc lesion.
authors.affiliation: Department of Microbiology & Immunology, Tulane University School of Medicine, New Orleans, LA 70112.
authors.forename: C A
authors.initials: CA
authors.lastname: Feghali
authors.forename: K L
authors.initials: KL
authors.lastname: Bost
authors.forename: D W
authors.initials: DW
authors.lastname: Boulware
authors.forename: L S
authors.initials: LS
authors.lastname: Levy
mesh_terms: D000328:Adult; D000368:Aged; D001706:Biopsy; D004591:Electrophoresis, Polyacrylamide Gel / Q000379:methods; D005260:Female; D005347:Fibroblasts / Q000276:immunology*; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D012260:Ribonucleases; D012595:Scleroderma, Systemic / Q000276:immunology*; D012867:Skin / Q000276:immunology; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D015850:Interleukin-6; D009687:Nuclear Proteins; D012333:RNA, Messenger; D012260:Ribonucleases