Sunahori Katsue, Yamamura Masahiro, Yamana Jiro, Takasugi Kouji, Kawashima Masanori, Yamamoto Hiroshi, Chazin Walter J, Nakatani Yuichi, Yui Satoru, Makino Hirofumi
Department of Medicine and Clinical Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Arthritis Res Ther. 2006;8(3):R69. doi: 10.1186/ar1939. Epub 2006 Apr 13.
S100A8 and S100A9, two Ca2+-binding proteins of the S100 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-kappaB) inhibitors. NF-kappaB 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-kappaB and p38 MAPK pathways in RA.
S100A8和S100A9是S100家族的两种钙结合蛋白，从中性粒细胞和单核细胞/巨噬细胞中作为异二聚体复合物（S100A8/A9）分泌出来。类风湿关节炎（RA）患者血清和滑液中S100A8、S100A9和S100A8/A9的水平均高于骨关节炎（OA）患者，其中S100A8/A9异二聚体最为普遍。通过双色免疫荧光标记发现，S100A8/A9抗原主要在RA滑膜组织（ST）中浸润的CD68 +巨噬细胞中表达。与OA患者的细胞相比，RA患者分离出的ST细胞自发释放出更多的S100A8/A9蛋白。S100A8/A9复合物以及S100A9同二聚体可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。p38丝裂原活化蛋白激酶（MAPK）抑制剂可显著抑制S100A8/A9介导的细胞因子产生，而核因子κB（NF-κB）抑制剂几乎可完全抑制。S100A8/A9刺激的单核细胞中可诱导NF-κB激活，但p38 MAPK抑制剂对此活性无抑制作用。这些结果表明，从活化的组织巨噬细胞细胞外分泌的S100A8/A9异二聚体可能通过激活RA中的NF-κB和p38 MAPK途径来放大促炎细胞因子反应。
