Mechanisms of cholera toxin-induced diarrhea.
In the pathogenesis of cholera, cyclic adenosine monophosphate, 5-hydroxytryptamine, prostaglandins, and the function of neuronal structures have been implicated. To elucidate the role of different isoforms of cyclooxygenase (COX)-1 and COX-2, selective COX-2 inhibitors were used. The selective COX-2 inhibitors NS-398 and DFU completely suppressed cholera toxin-induced prostaglandin E2 biosynthesis and caused a dose-dependent inhibition of cholera toxin-induced fluid secretion in the rat jejunum in vivo. Constitutive expression of COX-1 but also of COX-2 mRNA was found in mucosal scrapings of the rat jejunum. Cholera toxin had no effect on COX-1 as well as COX-2 mRNA expression. Treatment of rats with dexamethasone did not effect cholera toxin-induced prostaglandin E2 biosynthesis and did not influence the expression of COX-2 mRNA, further substantiating that cholera toxin does not cause an induction of COX-2 mRNA. Treatment of rats with E. coli lipopolysaccharide caused a marked increase in COX-2 mRNA expression that was inhibited by dexamethasone. In conclusion, the results provide evidence that cholera toxin, in addition to other mediators, uses prostaglandin E2 to exert its secretory effect and that in the case of cholera toxin prostaglandins are metabolized via COX-2.
Beubler
E
E
Department of Experimental and Clinical Pharmacology, Karl-Franzens-University of Graz, 8010 Graz, Austria. eckhard.beubler@kfunigraz.ac.at
Schuligoi
R
R
D000818:Animals; D002772:Cholera Toxin / Q000633:toxicity*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D003967:Diarrhea / Q000139:chemically induced* / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005663:Furans / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D005938:Glucocorticoids / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology*; D007527:Isoenzymes / Q000378:metabolism; D007583:Jejunum / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008565:Membrane Proteins; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology
C106876:5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D005663:Furans; D005938:Glucocorticoids; D007527:Isoenzymes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D009578:Nitrobenzenes; D012333:RNA, Messenger; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D003907:Dexamethasone; D002772:Cholera Toxin; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D015232:Dinoprostone