Inhibitory action of ethanol on cyclooxygenase-2 expression through suppression of the extracellular signal-related kinase-mediated pathway in rat alveolar macrophages.
The purpose of the present study was to elucidate the effects of ethanol on expression of cyclooxygenase in alveolar macrophages. Rat alveolar macrophages were collected by bronchoalveolar lavage and stimulated by lipopolysaccharide. Lipopolysaccharide-induced cyclooxygenase-2 expression and prostaglandin E2 production were inhibited by ethanol (100-200 mM) in a concentration-dependent manner. Ethanol at 100-200 mM concentration-dependently inhibited cyclooxygenase-2 mRNA expression. Lipopolysaccharide-stimulated phosphorylation of both extracellular signal-related kinase and p38 mitogen-activated protein kinase was also significantly inhibited by ethanol (50-200 mM). Cyclooxygenase-2 expression was significantly inhibited by U0126 but was not affected by SB203580. In the presence of SB203580, lipopolysaccharide-induced cyclooxygenase-2 expression was also inhibited by ethanol (50-200 mM). On the other hand, cyclooxygenase-1 was expressed constitutively in alveolar macrophages and cyclooxygenase-1 expression was affected neither by lipopolysaccharide nor ethanol. Lipopolysaccharide-induced expression of inducible nitric oxide synthase in alveolar macrophages was not affected by ethanol at 50-200 mM. These results suggest that lipopolysaccharide-induced expression of cyclooxygenase-2 is mediated by extracellular signal-related kinase but not by p38 kinase and that ethanol selectively attenuates cyclooxygenase-2 expression mainly by inhibiting activation of extracellular signal-related kinase.
Kato
Hirohisa
H
Department of Hygiene & Preventive Medicine, Yamagata University School of Medicine, Iida-Nishi 2-2-2, Yamagata 990-9585, Japan.
Negoro
Munetaka
M
Wakabayashi
Ichiro
I
D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000431:Ethanol / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000201:enzymology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008070:Lipopolysaccharides; C482199:lipopolysaccharide, E coli O55-B5; D000431:Ethanol; D019001:Nitric Oxide Synthase; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D048049:Extracellular Signal-Regulated MAP Kinases; D015232:Dinoprostone