Cadherin-11 regulates fibroblast inflammation
Cadherin-11 regulates fibroblast inflammation
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DOI：
10.1073/pnas.1019437108
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发表时间：
2011-05-17
影响因子：
11.1
通讯作者：
Brenner, Michael B.
中科院分区：
文献类型：
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作者：
Chang, Sook Kyung;Noss, Erika H.;Brenner, Michael B.
成纤维细胞是炎症的重要参与者。虽然不是白细胞，但它们在组织局部产生细胞因子、趋化因子和其他炎症因子的能力表明它们可能导致炎症性疾病。例如，类风湿性关节炎（RA）关节中的成纤维细胞是滑膜中IL-6和RANKL的主要来源，两者都是炎症和骨侵蚀的治疗靶点。之前，我们发现成纤维细胞可以被针对cadherin-11 （cad-11）的单克隆抗体靶向，cadherin-11是一种成纤维细胞选择性表达的间充质钙粘蛋白。通过关节肿胀和临床炎症评分评估，靶向cad-11可显著减轻炎症。然而，抗cad-11减少炎症的机制尚不清楚。在这里，我们发现cad-11接合诱导滑膜成纤维细胞分泌包括IL-6在内的促炎细胞因子。在诱导IL-6的过程中，Cad-11与tnf - α和IL-1 β有很强的协同作用。重要的是，cad-11激活MAP激酶和NF-kappa B诱导IL-6。与患有炎症性关节炎的野生型小鼠相比，cad-11突变小鼠炎症关节踝关节中的IL-6水平降低。因此，我们认为cad-11可以调节滑膜成纤维细胞，从而引发炎症因子，从而促进RA的炎症过程。
Fibroblasts are important participants in inflammation. Although not leukocytes, their capacity to produce cytokines, chemokines, and other inflammatory factors locally in tissues suggests that they can contribute to inflammatory diseases. For example, fibroblasts in a rheumatoid arthritis (RA) joint are a dominant source of IL-6 and RANKL in the synovium, both of which are therapeutic targets for inflammation and bone erosion. Previously, we found that fibroblasts can be targeted by mAb directed against cadherin-11 (cad-11), a mesenchymal cadherin that fibroblasts selectively express. Targeting cad-11 significantly reduced inflammation as assessed by joint swelling and clinical inflammation scores. However, the mechanism by which anti-cad-11 reduced inflammation was not known. Here, we show that cad-11 engagement induces synovial fibroblasts to secret proinflammatory cytokines including IL-6. Cad-11 engagement strongly synergized with TNF-alpha and IL-1 beta in the induction of IL-6. Importantly, cad-11 activated MAP kinases and NF-kappa B for IL-6 induction. IL-6 levels in ankles of inflamed joints were reduced in cad-11 mutant mice compared to wild-type mice with inflammatory arthritis. Thus, we suggest that cad-11 modulates synovial fibroblasts to evoke inflammatory factors that may contribute to the inflammatory process in RA.