Membrane-type serine protease-1/matriptase induces interleukin-6 and-8 in endothelial cells by activation of protease-activated receptor-2 -: Potential implications in atherosclerosis
Membrane-type serine protease-1/matriptase induces interleukin-6 and-8 in endothelial cells by activation of protease-activated receptor-2 -: Potential implications in atherosclerosis
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DOI：
10.1161/01.atv.0000258862.61067.14
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发表时间：
2007-04-01
影响因子：
8.7
通讯作者：
Ott, Ilka
中科院分区：
文献类型：
--
作者：
Seitz, Isabell;Hess, Sibylle;Ott, Ilka
目的 - 丝氨酸蛋白酶 MT-SP1/matriptase 在细胞迁移和基质降解中发挥重要作用。肝细胞生长因子 (HGF)、尿激酶型纤溶酶原激活剂 (uPA) 和蛋白酶激活受体 2 (PAR-2) 已被确定为 MT-SP1/matriptase 的体外底物。由于 PAR-2 在内皮细胞中表达并参与炎症过程，因此我们试图研究 MT-SP1/matriptase 对内皮细胞因子表达的影响，并分析血管细胞和动脉粥样硬化病变中 MT-SP1/matriptase 的表达。方法和结果 - 在内皮细胞中，重组 MT-SP1/matriptase 剂量依赖性诱导白细胞介素 (IL)-8 和 IL-6 mRNA 和蛋白表达依赖关于其蛋白水解活性。 MT-SP1/matriptase 时间依赖性诱导 p38 MAPK 和 p42/44 MAPK 磷酸化。抑制剂实验表明 p38 MAPK 和 PKC α 对于 IL-8 诱导是必需的。 PAR-2 下调被消除，PAR-2 过表达增强了 MT-SP1/matriptase 诱导的 IL-8 表达，作为 PAR-2 信号转导的证据。在人类动脉粥样斑块切除术中，MT-SP1/matriptase 在粘附于内皮的血细胞中表达。一致地，在分离的单核细胞中检测到基础 MT-SP1/matriptase 表达。单核细胞和内皮细胞共孵育导致 IL-8 释放增加，在内皮 PAR-2 和单核细胞 MT-SP1/matriptase 下调后，IL-8 释放减少。结论 - MT-SP1/matriptase 通过激活 PAR-2 诱导内皮细胞促炎细胞因子的释放。 MT-SP1/matriptase 在单核细胞中表达，因此，单核细胞 MT-SP1/matriptase 与内皮 PAR-2 的相互作用可能导致动脉粥样硬化。
Objective - The serine protease MT-SP1/matriptase plays an important role in cell migration and matrix degradation. Hepatocyte growth factor (HGF), urokinase-type plasminogen activator (uPA), and protease-activated receptor 2 (PAR-2) have been identified as in vitro substrates of MT-SP1/matriptase. Because PAR-2 is expressed in endothelial cells and contributes to inflammatory processes, we sought to investigate the effects of MT-SP1/matriptase on endothelial cytokine expression and analyzed MT-SP1/matriptase expression in vascular cells and atherosclerotic lesions.Methods and Results - In endothelial cells, recombinant MT-SP1/matriptase dose-dependently induced interleukin (IL)-8 and IL-6 mRNA and protein expression dependent on its proteolytic activity. MT-SP1/matriptase time-dependently induced phosphorylation of p38 MAPK and p42/44 MAPK. Inhibitor experiments revealed that p38 MAPK and PKC alpha were necessary for IL-8 induction. PAR-2 downregulation abolished and PAR-2 overexpression augmented MT-SP1/matriptase-induced IL-8 expression as evidence for PAR-2 signaling. In human atherectomies, MT-SP1/matriptase was expressed in blood cells adherent to the endothelium. Concordantly, basal MT-SP1/matriptase expression was detected in isolated monocytes. Coincubation of monocytes and endothelial cells resulted in an increased IL-8 release, which was reduced after downregulation of endothelial PAR-2 and monocytic MT-SP1/matriptase.Conclusion - MT-SP1/matriptase induces release of proinflammatory cytokines in endothelial cells through activation of PAR-2. MT-SP1/matriptase is expressed in monocytes, thus, interaction of monocytic MT-SP1/matriptase with endothelial PAR-2 may contribute to atherosclerosis.