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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Cadherin-11 regulates fibroblast inflammation
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Cadherin-11 regulates fibroblast inflammation

机译：Cadherin-11调节成纤维细胞炎症

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摘要

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-a and IL-1f) in the induction of IL-6. Importantly, cad-11 activated MAP kinases and NF-kB 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.
机译：成纤维细胞是炎症的重要参与者。尽管不是白细胞，但是它们在组织中局部产生细胞因子，趋化因子和其他炎性因子的能力表明它们可以导致炎性疾病。例如，类风湿关节炎（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标。以前，我们发现成纤维细胞可以被针对cadherin-11（cad-11）的mAb靶向，cadherin-11（cad-11）是一种成纤维细胞选择性表达的间质钙粘蛋白。根据关节肿胀和临床炎症评分，靶向cad-11可显着降低炎症。但是，抗cad-11减轻炎症的机制尚不清楚。在这里，我们显示cad-11参与诱导滑膜成纤维细胞分泌包括IL-6在内的促炎性细胞因子。在诱导IL-6中，Cad-11的参与与TNF-a和IL-1f有很强的协同作用。重要的是，cad-11激活了IL-6诱导的MAP激酶和NF-kB。与患有炎性关节炎的野生型小鼠相比，cad-11突变型小鼠的发炎关节脚踝中的IL-6水平降低。因此，我们建议cad-11调节滑膜成纤维细胞以引起可能促成RA炎症过程的炎症因子。

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    Sook Kyung Chang; Erika H. Noss; Mei Chen; Zhizhan Gu; Kirk Townsend; Rosa Grenha; Luis Leon; Soo Young Lee; David M. Lee; Michael B. Brenner;

  • 作者单位

    Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;

    Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;

    Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115,Pfizer Inc., 200 Cambridge Park Drive, Cambridge, MA 02141;

    Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;

    Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;

    Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115,LEBS-CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France;

    Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;

    Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;

    Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115,Novartis Institute for Biomedical Research, CHBS, WSJ-386.11.09, Novar-tis Pharma AG, AGCH-4056 Basel, Switzerland;

    Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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