Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining
Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease
Kim Midwood et al. Nature medicine. 15: 774-780 (2009)
Student: Chih-Yuan Kuo (郭芝源） Time: 15:10~16:00, Sep. 30, 2009
Commentator: Dr. Chrong-Reen Wang (王崇任老師） Place: Room 601
Abstract:
Rheumatoid arthritis (RA) is characterized by synovial inflammation and destruction of joint cartilage and bone which are mediated by persistent synthesis of proinflammatory cytokines, including tumor necrosis factor-α and interleukin-61. Tenascin-C (TN-C) is a hexameric glycoprotein component of the extracellular matrix. In RA, TN-C is highly expressed in both synovium and cartilage of diseased joints2. According to the previous studies, TLRs are highly expressed in synovial tissue from individuals with rheumatoid arthritis3. In this study, the authors hypothesized whether tenascin-C is a TLR ligand that contributes to the progression of inflammatory joint disease. First, the authors used zymosan and methylated BSA to induce acute synovitis in wild-type and Tnc-/- mice. These results indicate that expression of tenascin-C is required for persistent synovial inflammation and joint destruction. They also found that tenascin-C induces proinflammatory cytokine synthesis in human macrophages and synovial fibroblasts. The FBG domain of tenascin-C mediates cell activation, and induces joint inflammation in mice. By using Myd88-/- and TLR-4-/-mice, the authors further proved that FBG-mediated cytokine synthesis is dependent on TLR-4 expression and Myd88 signaling. In conclusion, this study identified a novel role for tenascin-C as an endogenous activator of TLR4 and demonstrated that tenascin-C is required for destructive joint inflammation.
References:
1. Williams, R.O. et al. Cytokine inhibitors in rheumatoid arthritis and other autoimmune diseases. Curr. Opin. Pharmacol. 7, 412–417 (2007)
2. Salter, D.M.et al. Tenascin is increased in cartilage and synovium from arthritic knees. Br. J. Rheumatol. 32, 780–786 (1993).
3. Radstake, T.R. et al. Expression of Toll-like receptors 2 and 4 in rheumatoid synovial tissue and regulation by proinflammatory cytokines interleukin-12 and interleukin-18 via interferon-g. Arthritis Rheum. 50, 3856–3865 (2004)