Cyclooxygenase 2 is a key enzyme for inflammatory cytokine-induced angiogenesis TAKASHI KUWANO * , SHINTARO NAKAO * , HIDETAKA YAMAMOTO † , MASAZUMI TSUNEYOSHI † , TOMOYA YAMAMOTO ‡ , MICHIHIKO KUWANO § and MAYUMI ONO * ,1 * Departments of Medical Biochemistry, † Anatomic Pathology, Pathological Sciences, and ‡ Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan; and § Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Fukuoka 830-0011, Japan 1 Correspondence: Department of *Medical Biochemistry, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: mayumi@biochem1.med.kyushu-u.ac.jp 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-1ß (IL-1ß) and tumor necrosis factor α (TNFα). IL-1ß enhanced expression of various prostanoids and this expression was blocked by COX2 selective inhibitors. IL-1ß 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-1ß-induced angiogenesis was blocked by an EP4 antagonist and a TXA2 receptor antagonist. IL-1ß 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-1ß-induced angiogenesis.—Kuwano, T., Nakao, S., Yamamoto, H., Tsuneyoshi, M., Yamamoto, T., Kuwano, M., Ono, M. Cyclooxygenase 2 is a key enzyme for inflammatory cytokine-induced angiogenesis. Key Words: COX2 • vascular endothelial growth factor • prostanoid • inflammatory disease
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Cyclooxygenase 2 is a key enzyme for inflammatory cytokine-induced angiogenesis
KUWANO, TAKASHI; NAKAO, SHINTARO; YAMAMOTO, HIDETAKA; TSUNEYOSHI, MASAZUMI; YAMAMOTO, TOMOYA; KUWANO, MICHIHIKO; ONO, MAYUMI
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, Volume 18 (2): 300
Fed of American Socs for Experimental Biology – Feb 1, 2004
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