β1 Integrin-mediated signaling induces intercellular adhesion molecule 1 and Fas on rheumatoid synovial cells and Fas-mediated apoptosis
β1 Integrin-mediated signaling induces intercellular adhesion molecule 1 and Fas on rheumatoid synovial cells and Fas-mediated apoptosis
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DOI：
10.1002/art.10941
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发表时间：
2003-05-01
影响因子：
--
通讯作者：
Tanaka, Y
中科院分区：
文献类型：
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作者：
Nakayamada, S;Saito, K;Tanaka, Y
Objective.类风湿性关节炎（RA）滑膜细胞通过整合素与炎性细胞以及细胞外基质相互作用。然而，β 1整合素与RA炎症过程的相关性仍不清楚。我们研究了β 1整合素介导的信号传导在RA中的作用。方法。通过FACScan评估细胞表面分子的表达。通过使用特异性单克隆抗体（mAb）和配体基质（如纤连蛋白或胶原蛋白）交联进行β 1整联蛋白的结合。为了确定酪氨酸激酶参与β 1整合素介导的信号传导，细胞用胞质内信号传导的各种抑制剂预处理或通过阳离子脂质体介导的转染用野生型粘着斑激酶（FAK）或FAK表达质粒的显性负截短转染。碘化丙啶和膜联蛋白V双染法检测滑膜细胞凋亡。β 1整合素在RA滑膜细胞上高度表达。通过交联以及通过配体基质的β 1整合素的接合显著上调细胞间粘附分子1（ICAM-1）和Fas的表达。整合素β 1诱导ICAM-1和Fas表达上调是通过酪氨酸激酶信号通路介导的，尤其是FAK。Fas介导的细胞早期凋亡变化被β 1交联放大。我们的研究结果表明，β 1整合素与细胞外基质的相互作用增强了RA滑膜细胞上ICAM-1和Fas的表达，以及Fas介导的滑膜细胞凋亡。这可能导致RA滑膜炎中观察到的通过Fas/Fas配体途径的自发生长停滞。
Objective. Rheumatoid arthritis (RA) synovial cells interact with inflammatory cells, as well as extracellular matrices, through integrins. However, the relevance of beta1 integrin to inflammatory processes in RA remains unclear. We examined the role of beta1 integrin-mediated signaling in RA.Methods. Expression of cell-surface molecules was assessed by FACScan. Engagement of beta1 integrins was performed by crosslinking using a specific monoclonal antibody (mAb) and ligand matrices such as fibronectin or collagen. To determine the involvement of tyrosine kinases in beta1 integrin-mediated signaling, the cells were pretreated with various inhibitors of intracytoplasmic signaling or were transfected with a wildtype focal adhesion kinase (FAK) or a dominant negative truncation of the FAK expression plasmid via cationic liposome-mediated transfection. Apoptosis of synovial cells was detected by double staining with propidium iodide and annexin V.Results. beta1 integrin was highly expressed on RA synovial cells. Engagement of beta1 integrins by crosslinking as well as by ligand matrices markedly up-regulated expression of intercellular adhesion molecule 1 (ICAM-1) and Fas. Up-regulation of ICAM-1 and Fas induced by beta1 integrin was mediated by the tyrosine kinase signaling pathway, especially involving FAK. Fas-mediated early apoptotic change in the cells was amplified by beta1 crosslinking.Conclusion. Our results suggest that interaction of beta1 integrins with extracellular matrix augments expression of ICAM-1 and Fas on RA synovial cells, as well as Fas-mediated apoptosis of synovial cells., This might lead to the spontaneous growth arrest through the Fas/Fas ligand pathway observed in, RA synovitis.