Brentano Fabia, Kyburz Diego, Gay Steffen
Department of Rheumatology, University Hospital Zürich, Gloriastrasse 25, CH-8091 Zurich, Switzerland.
Methods Mol Biol. 2009;517:329-43. doi: 10.1007/978-1-59745-541-1_20.
Rheumatoid arthritis (RA) is a chronic inflammatory disease that ultimately leads to the progressive destruction of cartilage and bone in numerous joints. There is mounting evidence for an important function of innate immunity in the pathogenesis of RA. Activation of cells by microbial components and also by endogenous molecules via Toll-like receptor (TLR) results in the production of a variety of proinflammatory cytokines, chemokines, and destructive enzymes, some of which can characteristically be found in RA.By immunohistochemistry we found elevated TLR2, 3, and 4 expressions in the rheumatoid synovium. In the synovial lining layer and at sites of invasion into cartilage, RA synovial fibroblasts (RASF) are the major cells expressing TLR2, 3, and 4. Stimulation of cultured RASF in vitro with the TLR2 ligand bacterial lipoprotein (bLP), the TLR3 ligand poly(I-C), and the TLR4 ligand LPS was shown to upregulate IL-6 as well as matrix metalloproteinases (MMPs) 1 and 3. These results suggest an important role for TLR2, 3, and 4 in the activation of synovial fibroblasts in RA leading to chronic inflammation and joint destruction.
类风湿性关节炎（RA）是一种慢性炎症性疾病，最终会导致多个关节的软骨和骨骼进行性破坏。越来越多的证据表明，固有免疫在类风湿性关节炎的发病机制中具有重要作用。微生物成分以及内源性分子通过Toll样受体（TLR）激活细胞，会导致多种促炎细胞因子、趋化因子和破坏性酶的产生，其中一些在类风湿性关节炎中具有特征性表现。通过免疫组织化学方法，我们发现类风湿滑膜中TLR2、3和4的表达升高。在滑膜衬里层以及侵入软骨的部位，类风湿滑膜成纤维细胞（RASF）是表达TLR2、3和4的主要细胞。体外使用TLR2配体细菌脂蛋白（bLP）、TLR3配体聚肌苷酸-聚胞苷酸（poly(I-C)）以及TLR4配体脂多糖（LPS）刺激培养的RASF，结果显示会上调白细胞介素-6以及基质金属蛋白酶（MMP）1和3的表达。这些结果表明TLR2、3和4在类风湿性关节炎滑膜成纤维细胞的激活过程中发挥重要作用，进而导致慢性炎症和关节破坏。
