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Vol. 297, Issue 3, 940-945, June 2001

Cholera Toxin Induces Prostaglandin Synthesis via Post-Transcriptional Activation of Cyclooxygenase-2 in the Rat Jejunum

Eckhard Beubler, Rufina Schuligoi, Ashok K. Chopra, Deborah A. Ribardo and Bernhard A. Peskar

Department of Experimental and Clinical Pharmacology, Karl-Franzens-University of Graz, Graz, Austria (E.B., R.S., B.A.P.); and Department of Microbiology and Immunology, the University of Texas Medical Branch, Galveston, Texas (A.K.C., D.A.R.)

The mechanisms of diarrhea in Asiatic cholera have been studied extensively. Cyclic AMP, 5-hydroxytryptamine, prostaglandins, and the function of neuronal structures have been implicated in the pathogenesis of cholera. To elucidate the role of the different isoforms (COX-1 and COX-2) of cyclooxygenase in cholera toxin (CT)-induced fluid secretion and intraluminal prostaglandin E2 (PGE2) release in the rat jejunum in vivo, the effects of the COX-2 inhibitors NS-398 ([N-(2-cyclohexaloxy-4-nitrophenyl)methanesulfonamide]) and DFU [5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone], and of the COX-1 inhibitor SC-560, were studied. Net fluid transport was measured gravimetrically and PGE2 by radioimmunoassay. COX-1 and COX-2 mRNA expression were determined by reverse transcription-polymerase chain reaction (RT-PCR) and COX-2 protein by Western blot analysis in mucosal scrapings. CT caused profuse net fluid secretion in all control rats. The COX-2 inhibitors NS-398 and DFU, but not the COX-1 inhibitor SC-560 or dexamethasone, dose-dependently inhibited CT-induced fluid secretion and PGE2 release. RT-PCR showed expression of COX-1 and of COX-2 mRNA in control rats. CT did not induce an increase and dexamethasone did not reduce COX-2 mRNA, whereas lipopolysaccharide caused a marked induction of COX-2 mRNA, which was inhibited by dexamethasone. A weak band of COX-2 protein was observed in controls; however, CT enhanced COX-2 levels, which remained unaffected by dexamethasone. It can be assumed that post-transcriptional modulation is responsible for CT-induced increase in COX-2 protein. COX-1 does not seem to be involved. Therefore, PGE2 produced by COX-2 seems to be responsible for the profuse fluid secretion induced by CT, and COX-2 appears to be a specific target for the treatment of Asiatic cholera.

0022-3565/01/2973-0940$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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