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Levels of NAD⁺-dependent 15-hydroxyprostaglandin dehydrogenase are reduced in inflammatory bowel disease: evidence for involvement of TNF-

Departments of ¹Medicine, ⁴Pediatrics, and ⁵Pathology, Weill Medical College of Cornell University, New York, New York; ²Department of Surgery, Tokyo Women's Medical University and Daini Hospital, Tokyo, Japan; ³Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky; and ⁶Departments of Pediatrics, Cell and Developmental Biology, and Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee

Submitted 26 July 2005 ; accepted in final form 26 September 2005

Increased amounts of PGE₂ have been detected in the inflamed mucosa of patients with inflammatory bowel disease (IBD). This increase has been attributed to enhanced synthesis rather than reduced catabolism of PGE₂. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) plays a major role in the catabolism of PGE₂. In this study, we investigated whether amounts of 15-PGDH were altered in inflamed mucosa from patients with IBD. Amounts of 15-PGDH protein and mRNA were markedly reduced in inflamed mucosa from patients with Crohn's disease and ulcerative colitis. In situ hybridization demonstrated that 15-PGDH was expressed in normal colonic epithelium but was virtually absent in inflamed colonic mucosa from IBD patients. Because of the importance of TNF- in IBD, we also determined the effects of TNF- on the expression of 15-PGDH in vitro. Treatment with TNF- suppressed the transcription of 15-PGDH in human colonocytes, resulting in reduced amounts of 15-PGDH mRNA and protein and enzyme activity. In contrast, TNF- induced two enzymes (cyclooxygenase-2 and microsomal prostaglandin E synthase-1) that contribute to increased synthesis of PGE₂. Overexpressing 15-PGDH blocked the increase in PGE₂ production mediated by TNF-. Taken together, these results suggest that reduced expression of 15-PGDH contributes to the elevated levels of PGE₂ found in inflamed mucosa of IBD patients. The decrease in amounts of 15-PGDH in inflamed mucosa can be explained at least, in part, by TNF--mediated suppression of 15-PGDH transcription.

prostaglandin E₂; inflammatory bowel disease; tumor necrosis factor-; cyclooxygenase

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