Cyclooxygenase 2 is a key enzyme for inflammatory cytokine-induced angiogenesis
Cyclooxygenase 2 is a key enzyme for inflammatory cytokine-induced angiogenesis
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DOI：
10.1096/fj.03-0473com
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发表时间：
2004-02-01
期刊：
影响因子：
4.8
通讯作者：
Ono, M
中科院分区：
文献类型：
--
作者：
Kuwano, T;Nakao, S;Ono, M
环氧合酶1（COX 1）和COX 2介导花生四烯酸代谢的限速步骤。COX 2 mRNA和蛋白质的表达通常在各种人类细胞类型中被炎性细胞因子如白细胞介素-1 β（IL-1 β）和肿瘤坏死因子α（TNF α）增强。IL-1 β增强各种前列腺素的表达，这种表达被COX 2选择性抑制剂阻断。IL-1 β在体外和体内均能显著诱导血管生成，COX 2选择性抑制剂可显著抑制IL-1 β诱导的血管生成，而血管内皮生长因子（VEGF）受体酪氨酸激酶抑制剂则不能。相反，COX 2选择性抑制剂仅部分阻断VEGF诱导的血管生成。EP 2、EP 4（前列腺素E2受体）激动剂和血栓素A2（TXA 2）受体激动剂在体外和体内诱导血管生成; IL-1 β诱导的血管生成被EP 4拮抗剂和TXA 2受体拮抗剂阻断。IL-1 β在COX 2基因敲除小鼠角膜中诱导的血管生成比野生型小鼠少得多。这是首次报道COX 2和一些前列腺素类在IL-1 β诱导的血管生成中起关键作用。
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.