Cyclooxygenase 2 expression by endothelin-1-stimulated mouse resident peritoneal macrophages in vitro.
Macrophages have been shown to produce endothelin and to play a role in the pathogenesis of neural damage after cerebral ischemia or vasospasm after subarachnoid hemorrhage. Cyclooxygenase 2 is induced during inflammation following brain insult and participates in inflammation-mediated neurotoxicity. However, it has not yet been established how endothelin-1 acts on cyclooxygenase 2 expression in macrophages. In the present study, we examined the effects of endothelin-1 on cyclooxygenase 2 expression and prostaglandin E2 production, and the effects of endothelin ET(A) and ET(B) receptor antagonists. Stimulation by endothelin-1 ranging from 10(-11) to 10(-9) M time and dose dependently increased the production of prostaglandin E2 and the expression of cyclooxygenase 2 protein without changing that of cyclooxygenase 1 protein, an effect which was inhibited by dexamethasone, nonsteroidal anti-inflammatory drugs and the selective endothelin ET(B) receptor antagonist, BQ788 (N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methyl-leucyl-D-L-me thoxycarbonyl-tryptophanyl-D-norleucine). The selective endothelin ET(A) receptor antagonist, BQ123 [cyclo (D-Trp-D-Asp-Pro-D-Val-Leu)] also inhibited these reactions, but its potency was less than that of the selective endothelin ET(B) receptor antagonist. Endothelin ET(A) and ET(B) receptor antagonists had no effects on cyclooxygenase 2 protein expression and prostaglandin E2 production in lipopolysaccharide-stimulated macrophages. We conclude that endothelin-1 increases cyclooxygenase 2 protein expression and prostaglandin E2 production via mainly endothelin ET(B) receptors and partly endothelin ET(A) receptors in macrophages; however, lipopolysaccharide increases both cyclooxygenase 2 protein expression and prostaglandin E2 production in pacrophages without involving endothelin ET(A) or ET(B) receptor-mediated processes.
Shimada
K
K
Department of Pharmacology, Nara Medical University, Kashihara, Japan. keijishi@nmugw.cc.naramed-u.ac.jp
Yonetani
Y
Y
Kita
T
T
Suzumura
A
A
Takayanagi
T
T
Nakashima
T
T
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D009578:Nitrobenzenes / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007527:Isoenzymes; D009578:Nitrobenzenes; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C086539:BQ 788; D003907:Dexamethasone; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D007213:Indomethacin