Cholera toxin induces prostaglandin synthesis via post- transcriptional activation of cyclooxygenase-2 in the rat jejunum

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

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

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-4nitrophenyl)methanesulfonamide]) and DFU [5,5-dimethyl-3-(3fiuorophenyl)-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 posttranscriptional 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.

Original languageEnglish (US)
Pages (from-to)940-945
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume297
Issue number3
StatePublished - Jun 2001

Fingerprint

Cholera Toxin
Jejunum
Cyclooxygenase 2
Transcriptional Activation
Prostaglandins
Fluids and Secretions
Dinoprostone
Dexamethasone
Cholera
Messenger RNA
Cyclooxygenase 2 Inhibitors
Reverse Transcription
Talin
Polymerase Chain Reaction
Cyclic AMP
Radioimmunoassay
Lipopolysaccharides
Diarrhea
Serotonin
Protein Isoforms

ASJC Scopus subject areas

  • Pharmacology

Cite this

Cholera toxin induces prostaglandin synthesis via post- transcriptional activation of cyclooxygenase-2 in the rat jejunum. / Beubler, Eckhard; Schuligoi, Rufina; Chopra, Ashok; Ribardo, Deborah A.; Peskar, Bernhard A.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 297, No. 3, 06.2001, p. 940-945.

Research output: Contribution to journalArticle

Beubler, Eckhard ; Schuligoi, Rufina ; Chopra, Ashok ; Ribardo, Deborah A. ; Peskar, Bernhard A. / Cholera toxin induces prostaglandin synthesis via post- transcriptional activation of cyclooxygenase-2 in the rat jejunum. In: Journal of Pharmacology and Experimental Therapeutics. 2001 ; Vol. 297, No. 3. pp. 940-945.
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T1 - Cholera toxin induces prostaglandin synthesis via post- transcriptional activation of cyclooxygenase-2 in the rat jejunum

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AB - 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-4nitrophenyl)methanesulfonamide]) and DFU [5,5-dimethyl-3-(3fiuorophenyl)-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 posttranscriptional 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.

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