Reduced expression of 15-PGDH contributes to elevated PGE₂ levels in inflamed mucosa of IBD patients

Increased amounts of prostaglandin (PG) E₂ have been detected in the inflamed mucosa of patients with inflammatory bowel disease (IBD). Multiple lines of evidence suggest an important role for PGE₂, and increased amounts of PGE₂ are detected at sites of intestinal inflammation and correlate with disease activity in IBD. Conversely, PGE₂ is important for maintaining mucosal homeostasis. It is important, therefore, to define the pathways that are dysregulated in IBD resulting in increased amounts of mucosal PGE₂. PGE₂ is catalyzed by cyclooxygenase (COX) and prostaglandin E synthase (PGES) and diminished by 15-hydroxyprostaglandin dehydrogenase (15-PGDH). Increased amounts of COX-2 and mPGES-1 have been detected in inflamed mucosa in IBD. In this study, we investigated whether amounts of 15-PGDH were altered in inflamed mucosa from patients with IBD. Reduced amounts of 15-PGDH were detected in inflamed intestinal mucosa from patients with IBD. Because of the importance of tumor necrosis factor-α (TNF-α) in IBD, we also determined the effects of TNF-α on the expression of 15-PGDH in vitro. Treatment with TNF-α increased amounts of PGE₂, COX-2 and mPGES-1 protein, but decreased 15-PGDH protein in human colonocytes. Overexpressing 15-PGDH blocked the increase in PGE ₂ production mediated by TNF-α. 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-α-mediated suppression of 15-PGDH transcription.