Cyclooxygenase 2 expression by endothelin-1-stimulated mouse resident peritoneal macrophages in vitro

Abstract

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 E 2 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 E 2 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-γ-methyl-leucyl- d- l-methoxycarbonyl-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 E 2 production in lipopolysaccharide-stimulated macrophages. We conclude that endothelin-1 increases cyclooxygenase 2 protein expression and prostaglandin E 2 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 E 2 production in pacrophages without involving endothelin ET A or ET B receptor-mediated processes.