Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Cell Line
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Cell Movement / drug effects
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Cells, Cultured
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Cornea / metabolism
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Cyclooxygenase 2
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Endothelium, Vascular / cytology
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / metabolism
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Gene Expression Regulation / drug effects
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Humans
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Inflammation Mediators / pharmacology*
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Interleukin-1 / pharmacology*
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / genetics
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Isoenzymes / metabolism*
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Membrane Proteins
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Mice
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Mice, Knockout
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Neovascularization, Physiologic / drug effects*
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Prostaglandin-Endoperoxide Synthases / genetics
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Prostaglandin-Endoperoxide Synthases / metabolism*
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Prostaglandins / metabolism
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Prostaglandins / pharmacology
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Receptors, Prostaglandin E / agonists
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Receptors, Prostaglandin E / antagonists & inhibitors
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Receptors, Prostaglandin E / metabolism
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Receptors, Thromboxane A2, Prostaglandin H2 / agonists
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Receptors, Thromboxane A2, Prostaglandin H2 / antagonists & inhibitors
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Receptors, Thromboxane A2, Prostaglandin H2 / metabolism
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Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors
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Receptors, Vascular Endothelial Growth Factor / metabolism
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Tumor Necrosis Factor-alpha / pharmacology
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Vascular Endothelial Growth Factor A / pharmacology
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Inflammation Mediators
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Interleukin-1
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Isoenzymes
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Membrane Proteins
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Prostaglandins
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Receptors, Prostaglandin E
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Receptors, Thromboxane A2, Prostaglandin H2
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Tumor Necrosis Factor-alpha
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Vascular Endothelial Growth Factor A
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Cyclooxygenase 2
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases
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Receptors, Vascular Endothelial Growth Factor