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 inducible factor 1 (HIF-1) and nuclear factor-κB (NF-κB). Knockout of either HIF-1 or (IKKβ-dependent) NF-κB pathways in intestinal epithelial cells promotes inflammatory disease in murine models of colitis. Both HIF-1 and NF-κB 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-κB 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.

Abbreviations used in this paper: cIAP-2, cellular inhibitor of apoptosis protein 2, DAI, disease activity index, DMOG, dimethyloxalylglycine, DSS, dextran-sodium sulfate, HIF, hypoxia inducible factor, IL, interleukin, MPO, myeloperoxidase, NF-κB, nuclear factor κB, TNF, tumor necrosis factor