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

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

Author information

1
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

Abstract

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.

PMID:
21223583
PMCID:
PMC3241348
DOI:
10.1186/ar3221
[Indexed for MEDLINE]
Free PMC Article

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