The hydroxylase inhibitor dimethyloxalylglycine is protective in a murine model of colitis

Background & Aims: Prolyl and asparaginyl hydroxylases are key oxygen-sensing enzymes that confer hypoxic sensitivity to transcriptional regulatory pathways including the hypoxia inducibl e factor 1 (HIF-1) and nuclear factor-kappa B (NF-kappa B). Knockout of either HIF-1 or (IKK beta-dependent) NF-kappa B pathways in intestinal epithelial cells promotes inflammatory disease in murine models of colitis. Both HIF-1 and NF-kappa B pathways are repressed by the action of hydroxylases through the hydroxylation of key regulatory molecules. Methods: In this study we have investigated the effects of the hydroxylase inhibitor dimethyloxalylglycine (DMOG) on Caco-2 intestinal epithelial cells in vitro and in a dextran sodium sulfate-induced model of murine colitis. Results: DMOG induces both HIF-1 and NF-kappa B activity in cultured intestinal epithelial cells, and is profoundly protective in dextran-sodium sulfate colitis in a manner that is at least in part reflected by the development of an anti-apoptotic phenotype in intestinal epithelial cells, which we propose reduces epithelial barrier dysfunction. Conclusions: These data show that hydroxylase inhibitors such as DMOG represent a new strategy for the treatment of inflammatory bowel disease.