Modulation by endothelin-1 of lipopolysaccharide-induced cyclooxygenase 2 expression in mouse peritoneal macrophages.
We investigated the modulation by endothelin-1 of lipopolysaccharide-induced cyclooxygenase 2 expression and prostaglandin E2 production by mouse peritoneal macrophages. Our previous report showed that endothelin-1 at concentrations above 10(-11) M induced cyclooxygenase 2 expression through mainly endothelin ET(B) receptors and that an endothelin ET(B) receptor-mediated process was not involved in cyclooxygenase 2 activation in macrophages stimulated by lipopolysaccharide for 4 h. In the present study, when macrophages were stimulated by lipopolysaccharide for 12 h in the presence of endothelin-1 (10(-15) to 10(-8) M), cyclooxygenase 2 expression and prostaglandin E2 production were enhanced by 1.2- to 1.6-fold. The endothelin ET(B) receptor selective antagonist, BQ788 (N-cis-2,6-dimethylpiperidino-carbonyl-L-gamma-methyl-leucyl-D-L-m ethoxycarbonyl-tryptophanyl-norleucine), significantly inhibited this synergistic effect of endothelin-1. In addition, the cyclooxygenase 2-selective inhibitor, NS398 (N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide), also suppressed this effect. Western blot analysis showed that the endothelin ET(B) receptor was up-regulated by lipopolysaccharide in a time- and concentration-dependent manner, and that this up-regulation was inhibited by NS398. From these results, we conclude that endothelin-1 promotes lipopolysaccharide-induced cyclooxygenase 2 activation in the delayed phase through endothelin ET(B) receptors up-regulated by lipopolysaccharide.
Shimada
K
K
Department of Pharmacology, Nara Medical University, Kashihara, Japan. keijishi@nmu-gw.cc.naramed-u.ac.jp
Kita
T
T
Yonetani
Y
Y
Suzumura
A
A
Takayanagi
T
T
Nakashima
T
T
D000818:Animals; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009578:Nitrobenzenes / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000187:drug effects* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007527:Isoenzymes; D008070:Lipopolysaccharides; D009578:Nitrobenzenes; D009842:Oligopeptides; D010880:Piperidines; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C086539:BQ 788; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone