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

Arthritis Research & Therapy, Jan 2011

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.

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

Sandeep K Agarwal 0 Minghua Wu 0 Christopher K Livingston 1 Donald H Parks 1 Maureen D Mayes 0 Frank C Arnett 0 Filemon K Tan 0 0 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 1 Division of Plastic and Reconstructive Surgery, Department of Surgery, The University of Texas Health Science Center at Houston , 6431 Fannin Avenue, Houston, TX 77030 , USA 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 IFNa2. The ability of IFNa2 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: IFNa2 increased TLR3 expression on human dermal fibroblasts, which resulted in enhanced TLR3-induced IL-6 production. SSc fibroblasts have an augmented TLR3 response to IFNa2 relative to control fibroblasts. Pretreatment of fibroblasts with transforming growth factor (TGF)-b increased TLR3 induction by IFNa2, but coincubation of TGF-b did not alter TLR3 induction by IFN. Furthermore, IFNa2 inhibits but does not completely block the induction of connective tissue growth factor and collagen expression by TGF-bin 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. - Introduction Systemic sclerosis (SSc), or scleroderma, is a multisystem autoimmune disease clinically characterized by progressive fibrosis of the skin and internal organs. Pathologically, SSc exhibits three cardinal features: inflammation and autoimmunity, vasculopathy and excessive extracellular matrix (ECM) deposition [1]. The ECM consists of collagens, proteoglycans, fibrillins and other matrix molecules [2]. Located within this matrix are fibroblasts and myofibroblasts, key effectors of the fibrotic process. Resident and infiltrating cells in the dermis secrete soluble mediators, such as transforming growth factor b (TGF-b), that activate fibroblasts and induce differentiation into myofibroblasts [3,4]. The myofibroblasts subsequently produce large amounts of ECM, leading to fibrosis. In addition to their role in ECM deposition, dermal fibroblasts and myofibroblasts are capable of secreting inflammatory cytokines and chemokines, such as interleukin (IL)-6 and CC chemokine ligand 2 (CCL-2), important inflammatory mediators in SSc pathogenesis [5-8]. Thus, fibroblasts also may contribute to the development of dermal fibrosis through the production of these inflammatory mediators. Current paradigms point toward systemic immune dysregulation as a central process that ultimately may lead to fibroblast activation. Biopsies of early SSc skin demonstrate perivascular infiltrates of mononuclear inflammatory cells, which produce cytokines and chemokines that recruit inflammatory cells and promote ECM deposition [9]. More recent studies in patients with SSc have identified dysregulation of type I interferon (IFN) pathways similar to those seen in patients with systemic lupus erythematosus (SLE) [10-12]. Gene expression profiling of peripheral blood has demonstrated the presence of a type I IFN signature in patients with SSc [12]. These findings have been confirmed in both circulating CD14+ monocytes and CD4+ T-cells, as well as in skin biopsies from patients with SSc compared with healthy controls [13-15]. Together these data demonstrate the presence of a type I IFN signature in circulating blood cells and a major target organ (skin) in patients with SSc. Type I IFNs are potent regulators of the immune system, where they modulate the differentiation, survival, proliferation and cytokine production of T-cells, B-cells and dendritic cells. Among the critical immunoregulatory functions of IFN is its ability to stimulate the expression of Toll-like receptors (TLRs) on dendritic cells. TLRs are a family of germ line-encoded proteins that serve as pattern recognition receptors capable of recognizing highly conserved motifs present in infectious microorganisms cal (...truncated)


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Sandeep K Agarwal, Minghua Wu, Christopher K Livingston, Donald H Parks, Maureen D Mayes, Frank C Arnett, Filemon K Tan. Toll-like receptor 3 upregulation by type I interferon in healthy and scleroderma dermal fibroblasts, Arthritis Research & Therapy, 2011, pp. R3, 13, DOI: 10.1186/ar3221