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1 Department of Medicine, Weill Medical College of Cornell University, New York, New York, USA; Department of Surgery, Tokyo Women's Medical University Daini Hospital, Tokyo, Japan
2 Department of Medicine, Weill Medical College of Cornell University, New York, New York, USA
3 Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky, USA
4 Department of Pediatrics, Weill Medical College of Cornell University, New York, New York, USA
5 Department of Pathology, Weill Medical College of Cornell University, New York, New York, USA
6 Departments of Pediatrics and Cell & Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
* To whom correspondence should be addressed. E-mail: ajdannen{at}med.cornell.edu.
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,
protein and enzyme activity. In contrast, TNF- induced two enzymes (COX-2,
mPGES-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.
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