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Activation of synovial fibroblasts via Toll-like receptor signaling

Toll-like receptors (TLRs) are pattern recognition receptors of the innate immune system. TLR activation has a profound influence on the subsequent adaptive immune responses by influencing T-cell differentiation towards a Th1 phenotype. Whether TLR signaling is involved in autoimmune phenomena is not known. The presence of TLR ligands in the joints of patients with rheumatoid arthritis and the fact that direct injection of bacterial peptidoglycan, a TLR2 agonist, and bacterial DNA, a TLR9 agonist, results in a transient arthritis in mice suggests that TLR signaling is of importance in the development of arthritis. Furthermore, recent evidence indicates that stimulation of TLR9 on B lymphocytes by immune complexes containing chromatin drives production of autoantibodies. We have detected TLR2 expression on synovial fibroblasts of patients with rheumatoid arthritis by immunohistochemistry. Cultured human synovial fibroblasts expressed functional TLR2 in vitro. Stimulation of synovial fibroblasts with the TLR2 ligand peptidoglycan induced a significant upregulation of the expression of matrix metalloproteinases and the cytokine IL-6. Furthermore, chemokine secretion by rheumatoid arthritis synovial fibroblasts was significantly increased. These results argue that the local presence of bacterial products may induce a local inflammatory response by signaling via TLR2. Blockade of TLR signaling pathways may therefore represent a promising new therapeutic option for rheumatoid arthritis.

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Kyburz, D., Pierer, M., Rethage, J. et al. Activation of synovial fibroblasts via Toll-like receptor signaling. Arthritis Res Ther 5 (Suppl 3), 40 (2003).

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