Cyclooxygenase 2 is a key enzyme for inflammatory cytokine-induced angiogenesis.
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.
Kuwano
Takashi
T
Department of Medical Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Nakao
Shintaro
S
Yamamoto
Hidetaka
H
Tsuneyoshi
Masazumi
M
Yamamoto
Tomoya
T
Kuwano
Michihiko
M
Ono
Mayumi
M
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003315:Cornea / Q000378:metabolism; D051546:Cyclooxygenase 2; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D011453:Prostaglandins / Q000378:metabolism / Q000494:pharmacology; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018836:Inflammation Mediators; D007375:Interleukin-1; D007527:Isoenzymes; D008565:Membrane Proteins; D011453:Prostaglandins; D018078:Receptors, Prostaglandin E; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D040262:Receptors, Vascular Endothelial Growth Factor