Roles of Rac and cytosolic phospholipase A2 in the intracellular signalling in response to titanium particles
Roles of Rac and cytosolic phospholipase A2 in the intracellular signalling in response to titanium particles
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DOI：
10.1016/s0898-6568(02)00118-3
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发表时间：
2003-03-01
影响因子：
4.8
通讯作者：
Kim, JH
中科院分区：
文献类型：
--
作者：
Lee, SS;Woo, CH;Kim, JH
钛颗粒是植入物常用的假体材料之一，与假体周围骨溶解等发病机制密切相关。在本研究中，我们致力于了解外源性钛刺激的大鼠成纤维细胞的细胞内信号通路。瞬时转染后的报告基因分析表明，外源钛以剂量依赖的方式刺激c-fos血清反应元件(SRE)依赖的荧光素酶活性。此外，Rac GTP酶在钛对c-fos SRE的信号转导中起重要作用。此外，胞浆磷脂酶AZ(CPLA(2))的抑制剂MAFP、5-脂氧合酶(5-LO)的抑制剂MK886或环氧合酶(COX)的一般抑制剂吲哚美辛也显著抑制了钛诱导的SRE的激活，提示CPLA(2)和随后的花生四烯酸(AA)代谢在钛向c-fos SRE的信号转导中起中介作用。与这些结果一致的是，暴露于钛颗粒的细胞内白三烯B-4(LTB4)和前列腺素E-2(PGE(2))水平呈RAC依赖性升高。(C)2002 Elsevier Science Inc.保留所有权利。
Titanium (Ti) particle is one of the prosthetic materials commonly used in implantation and has frequently been implicated in pathogenesis such as periprosthetic osteolysis. In the present study, we undertook to understand the intracellular signalling pathway stimulated by exogenous Ti at Rat-2 fibroblasts. By reporter gene analysis following transient transfections, exogenous Ti was shown to stimulate c-fos serum response element (SRE)-dependent luciferase activities in a dose-dependent manner. In addition, Ti-induced SRE activation was shown to be dramatically repressed by RacN17, a dominant negative mutant of Rac1, suggesting that Rac GTPase is essential for the signalling of Ti to c-fos SRE. Furthermore, pretreatment with MAFP, an inhibitor of cytosolic phospholipase AZ (cPLA(2)), MK886, an inhibitor of 5-lipoxygenase (5-LO), or indomethacin, a general inhibitor of cyclooxygenase (COX), also significantly repressed Ti-induced SRE activation, suggesting mediatory roles of cPLA(2) and subsequent arachidonic acid (AA) metabolisms to leukotrienes (LTs) and prostaglandins (PGs) in the Ti signalling to c-fos SRE. Consistent with these results, intracellular levels of leukotriene B-4 (LTB4) and prostaglandin E-2 (PGE(2)) were Rac-dependently elevated in cells exposed to Ti particles. (C) 2002 Elsevier Science Inc. All rights reserved.