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

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 IFN alpha 2. The ability of IFN alpha 2 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: IFN alpha 2 increased TLR3 expression on human dermal fibroblasts, which resulted in enhanced TLR3-induced IL-6 production. SSc fibroblasts have an augmented TLR3 response to IFN alpha 2 relative to control fibroblasts. Pretreatment of fibroblasts with transforming growth factor (TGF)-beta increased TLR3 induction by IFN alpha 2, but coincubation of TGF-beta did not alter TLR3 induction by IFN. Furthermore, IFN alpha 2 inhibits but does not completely block the induction of connective tissue growth factor and collagen expression by TGF-beta in 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.