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Open Access Research article

Arthritis is associated with T-cell-induced upregulation of Toll-like receptor 3 on synovial fibroblasts

Wenhua Zhu12, Liesu Meng12, Congshan Jiang12, Xiaojing He12, Weikun Hou12, Peng Xu3, Heng Du4, Rikard Holmdahl5 and Shemin Lu126*

Author Affiliations

1 Department of Genetics and Molecular Biology, Xi'an Jiaotong University School of Medicine, Yanta West Road 76, Xi'an, Shaanxi 710061, People's Republic of China

2 Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Yanta West Road 76, Xi'an, Shaanxi 710061, People's Republic of China

3 Department of Bone and Joint Diseases, Xi'an Red Cross Hospital, Nanguo Road 76, Xi'an, Shaanxi 710054, People's Republic of China

4 Department of Orthopedics, First Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Yanta West Road 277, Xi'an, Shaanxi 710061, People's Republic of China

5 Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Alfred Nobels Allé 8, Huddinge, SE-171 77 Stockholm, Sweden

6 Department of Epidemiology and Health Statistics, Xi'an Jiaotong University School of Medicine, Yanta West Road 76, Xi'an, Shaanxi 710061, People's Republic of China

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Arthritis Research & Therapy 2011, 13:R103  doi:10.1186/ar3384

Published: 27 June 2011

Abstract

Introduction

Toll-like receptors (TLRs) are likely to play crucial roles in the pathogenesis of rheumatoid arthritis (RA). The aim of this study was to determine the key TLRs in synovium and explore their roles in the activation of fibroblast-like synoviocytes (FLSs) mediated by T cells in arthritis.

Methods

Pristane-induced arthritis (PIA) was established by subcutaneous injection with pristane at the base of the rat's tail. TLR expression in synovium from PIA rats was detected at different time points by performing real-time PCR. Polyinosinic:polycytidylic acid (poly(I:C)) was intra-articularly administrated to PIA rats, and arthritis was monitored macroscopically and microscopically. Synovial TLR3 was detected by immunohistochemical staining. Rat FLSs were stimulated with pristane-primed T cells or pristane-primed, T-cell conditioned medium. The intervention of TLR3 in FLSs was achieved by specific short-hairpin RNA (shRNA) or an antibody. The migration ability of FLSs was measured by using the scratch test, and gene expression was detected by using real-time PCR. FLSs from RA patients were stimulated with various cytokines and TLR ligands, and TLR3 expression was detected by performing real-time PCR. In addition, with different concentrations of poly(I:C) stimulation, TLR3 expression of FLSs from RA patients and patients with osteoarthritis (OA) was compared.

Results

Synovium TLR3 displayed early and persistent overexpression in PIA rats. TLR3 was expressed in FLSs, and local treatment with poly(I:C) synergistically aggravated the arthritis. Rat FLSs co-cultured with pristane-primed T cells showed strengthened migration ability and significant upregulation of TLR3, IFN-β, IL-6 and matrix metalloproteinase 3 (MMP3) expression, which could also be induced by pristane-primed, T-cell conditioned medium. The upregulation of cytokines and MMPs was blocked by shRNA or TLR3 antibodies. In RA FLSs with cytokine or TLR ligand stimulation, TLR3 expression exhibited remarkable upregulation. Furthermore, RA FLSs showed higher reactivity than OA FLSs to poly(I:C).

Conclusions

TLR3 in the synovium of PIA rats was overexpressed, and activation of the TLR3 signaling pathway could aggravate this arthritis. The induction of TLR3 in FLSs resulted from T cell-derived inflammatory stimulation and could further mediate FLS activation in arthritis. We conclude that TLR3 upregulation of FLSs activated by T cells results in articular inflammation.