title: Toll-like receptor 3 upregulation by type I interferon in healthy and scleroderma dermal fibroblasts.
abstract: BACKGROUND
  Increased levels of genes in the type I interferon (IFN) pathway have been observed in patients with systemic sclerosis (SSc), or scleroderma. How type I IFN regulates the dermal fibroblast and its participation in the development of dermal fibrosis is not known. We hypothesized that one mechanism by which type I IFN may contribute to dermal fibrosis is through upregulation of specific Toll-like receptors (TLRs) on dermal fibroblasts. Therefore, we investigated the regulation of TLR expression on dermal fibroblasts by IFN.
  
  
  METHODS
  The expression of TLRs was assessed in cultured dermal fibroblasts from control and SSc patients stimulated with IFNα2. The ability of IFNα2 to regulate TLR-induced interleukin (IL)-6 and CC chemokine ligand 2 production was also assessed. Immunohistochemical analyses were performed to determine whether TLR3 was expressed in skin biopsies in the bleomycin-induced skin fibrosis model and in patients with SSc.
  
  
  RESULTS
  IFNα2 increased TLR3 expression on human dermal fibroblasts, which resulted in enhanced TLR3-induced IL-6 production. SSc fibroblasts have an augmented TLR3 response to IFNα2 relative to control fibroblasts. Pretreatment of fibroblasts with transforming growth factor (TGF)-β increased TLR3 induction by IFNα2, but coincubation of TGF-β did not alter TLR3 induction by IFN. Furthermore, IFNα2 inhibits but does not completely block the induction of connective tissue growth factor and collagen expression by TGF-βin fibroblasts. TLR3 expression was observed in dermal fibroblasts and inflammatory cells from skin biopsies from patients with SSc as well as in the bleomycin-induced skin fibrosis model.
  
  
  CONCLUSIONS
  Type I IFNs can increase the inflammatory potential of dermal fibroblasts through the upregulation of TLR3.
authors.affiliation: Division of Rheumatology and Clinical Immunogenetics, Department of Internal Medicine, The University of Texas Health Science Center at Houston, 6431 Fannin Avenue, Houston, TX 77030, USA. Sandeep.K.Agarwal@uth.tmc.edu
authors.forename: Sandeep K
authors.initials: SK
authors.lastname: Agarwal
authors.forename: Minghua
authors.initials: M
authors.lastname: Wu
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Livingston
authors.forename: Donald H
authors.initials: DH
authors.lastname: Parks
authors.forename: Maureen D
authors.initials: MD
authors.lastname: Mayes
authors.forename: Frank C
authors.initials: FC
authors.lastname: Arnett
authors.forename: Filemon K
authors.initials: FK
authors.lastname: Tan
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005347:Fibroblasts / Q000276:immunology* / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D007150:Immunohistochemistry; D016898:Interferon-alpha / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D012595:Scleroderma, Systemic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D012867:Skin / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051196:Toll-Like Receptor 3 / Q000096:biosynthesis / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D016898:Interferon-alpha; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3