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The mechanisms of S100A8/A9-mediated macrophage activation in rheumatoid arthritis

S100A8/A9介导的巨噬细胞活化在类风湿性关节炎中的机制

基本信息

批准号：
18591111
负责人：
YAMAMURA Masahiro
金额：
$ 2.32万
依托单位：
Aichi Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591111/
关键词：
rheumatoid arthritis macrophages S100A8 A9 protein cytokines signal transduction

项目摘要

S100A8 and S 100A9, two Ca_<2+->binding proteins of the S 100 family, are secreted as a heterodimeric complex (S100A8/A9) from neutrophils and monocytes/macrophages. Serum and synovial fluid levels of S100A8, S100A9, and S100A8/A9 were all higher in patients with rheumatoid arthritis (RA) than in patients with osteoarthritis (OA), with the S100A8/A9 heterodimer being prevalent. By two-color immunofluorescence labeling, S100A8/A9 antigens were found to be expressed mainly by infiltrating CD68_+ macrophages in RA synovial tissue (ST). Isolated ST cells from patients with RA spontaneously released larger amounts of S100A8/A9 protein than did the cells from patients with OA. S100A8/A9 complexes, as well as S100A9 homodimers, stimulated the production of proinflammatory cytokines, such as tumor necrosis factor alpha, by purified monocytes and in vitro-differentiated macrophages. S100A8/A9-mediated cytokine production was suppressed significantly by p38 mitogen-activated protein kinase (MAPK) inhibitors and almost completely by nuclear factor kappa B (NF-κB) inhibitors. NF-κB activation was induced in S100A8/A9-stimulated monocytes, but this activity was not inhibited by p38 MAPK inhibitors. These results indicate that the S100A8/A9 heterodimer, secreted extracellularly from activated tissue macrophages, may amplify proinflammatory cytokine responses through activation of NF-KB and p38 MAPK pathways in RA.

S100 A8和S100 A9是S100家族的两种钙结合蛋白，由中性粒细胞和单核/巨噬细胞分泌，形成异源二聚体复合物（S100 A8/A9）。类风湿性关节炎（RA）患者血清和滑液中S100 A8、S100 A9和S100 A8/A9的水平均高于骨关节炎（OA）患者，其中S100 A8/A9异源二聚体占优势。双色免疫荧光标记显示，S100 A8/A9抗原主要表达于RA滑膜组织中浸润的CD 68+巨噬细胞。从RA患者中分离的ST细胞自发释放的S100 A8/A9蛋白量比从OA患者中分离的细胞释放的S100 A8/A9蛋白量要多。S100 A8/A9复合物以及S100 A9同源二聚体刺激纯化的单核细胞和体外分化的巨噬细胞产生促炎细胞因子，如肿瘤坏死因子α。S100 A8/A9介导的细胞因子的产生被p38丝裂原活化蛋白激酶（MAPK）抑制剂显著抑制，并且几乎完全被核因子κ B（NF-κB）抑制剂抑制。NF-κB活化在S100 A8/A9刺激的单核细胞中被诱导，但这种活性不被p38 MAPK抑制剂抑制。这些结果表明，S100 A8/A9异源二聚体，从活化的组织巨噬细胞分泌的细胞外，可以放大促炎细胞因子反应，通过激活NF-κ B和p38 MAPK途径在RA。