Kuwano Takashi, Nakao Shintaro, Yamamoto Hidetaka, Tsuneyoshi Masazumi, Yamamoto Tomoya, Kuwano Michihiko, Ono Mayumi
Department of Medical Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
FASEB J. 2004 Feb;18(2):300-10. doi: 10.1096/fj.03-0473com.
Cyclooxygenase1 (COX1) and COX2 mediate the rate-limiting step in arachidonic acid metabolism. Expression of COX2 mRNA and protein is often enhanced in various human cell types by inflammatory cytokines such as interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNFalpha). IL-1beta enhanced expression of various prostanoids and this expression was blocked by COX2 selective inhibitors. IL-1beta markedly induced angiogenesis in vitro and in vivo, which was significantly inhibited by COX2 selective inhibitors but not by a vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor. In contrast, COX2 selective inhibitors only partially blocked VEGF-induced angiogenesis. EP2, EP4 (prostaglandin E2 receptors) agonists and thromboxane A2 (TXA2) receptor agonists induced angiogenesis in vitro and in vivo; IL-1beta-induced angiogenesis was blocked by an EP4 antagonist and a TXA2 receptor antagonist. IL-1beta induced much less angiogenesis in cornea of COX2 knockout mice than that of wild-type mice. This is the first report that COX2 and some prostanoids play a key role in IL-1beta-induced angiogenesis.
环氧化酶1（COX1）和COX2介导花生四烯酸代谢的限速步骤。在多种人类细胞类型中，诸如白细胞介素-1β（IL-1β）和肿瘤坏死因子α（TNFα）等炎性细胞因子常常会增强COX2信使核糖核酸（mRNA）和蛋白质的表达。IL-1β增强了各种前列腺素的表达，而这种表达被COX2选择性抑制剂所阻断。IL-1β在体外和体内均显著诱导血管生成，这被COX2选择性抑制剂显著抑制，但未被血管内皮生长因子（VEGF）受体酪氨酸激酶抑制剂抑制。相比之下，COX2选择性抑制剂仅部分阻断VEGF诱导的血管生成。前列腺素E2受体（EP2、EP4）激动剂和血栓素A2（TXA2）受体激动剂在体外和体内均诱导血管生成；IL-1β诱导的血管生成被EP4拮抗剂和TXA2受体拮抗剂阻断。与野生型小鼠相比，IL-1β在COX2基因敲除小鼠角膜中诱导的血管生成要少得多。这是首篇报道COX2和一些前列腺素在IL-1β诱导的血管生成中起关键作用的文章。
