Toll-like receptor 3 upregulation by type I interferon in healthy and scleroderma dermal fibroblasts

Arthritis Res Ther. 2011 Jan 11;13(1):R3. doi: 10.1186/ar3221.


Introduction: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Fibroblasts / immunology*
  • Fibroblasts / metabolism
  • Fibrosis
  • Humans
  • Immunohistochemistry
  • Interferon-alpha / immunology*
  • Interferon-alpha / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Real-Time Polymerase Chain Reaction
  • Scleroderma, Systemic / immunology*
  • Scleroderma, Systemic / metabolism
  • Scleroderma, Systemic / pathology
  • Skin / immunology*
  • Skin / metabolism
  • Skin / pathology
  • Toll-Like Receptor 3 / biosynthesis
  • Toll-Like Receptor 3 / immunology*
  • Up-Regulation


  • Interferon-alpha
  • TLR3 protein, human
  • Toll-Like Receptor 3