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

Increased amounts of PGE(2) 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 PGE(2). 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) plays a major role in the catabolism of PGE(2). 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-alpha in IBD, we also determined the effects of TNF-alpha on the expression of 15-PGDH in vitro. Treatment with TNF-alpha 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-alpha induced two enzymes (cyclooxygenase-2 and microsomal prostaglandin E synthase-1) that contribute to increased synthesis of PGE(2). Overexpressing 15-PGDH blocked the increase in PGE(2) production mediated by TNF-alpha. Taken together, these results suggest that reduced expression of 15-PGDH contributes to the elevated levels of PGE(2) 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-alpha-mediated suppression of 15-PGDH transcription.

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