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-kappaB (NF-kappaB). Knockout of either HIF-1 or (IKKbeta-dependent) NF-kappaB pathways in intestinal epithelial cells promotes inflammatory disease in murine models of colitis. Both HIF-1 and NF-kappaB 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-kappaB 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.
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-kappaB (NF-kappaB). Knockout of either HIF-1 or (IKKbeta-dependent) NF-kappaB pathways in intestinal epithelial cells promotes inflammatory disease in murine models of colitis. Both HIF-1 and NF-kappaB 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 murinecolitis. RESULTS:DMOG induces both HIF-1 and NF-kappaB activity in cultured intestinal epithelial cells, and is profoundly protective in dextran-sodium sulfatecolitis 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.
Authors: Douglas J Kominsky; Simon Keely; Christopher F MacManus; Louise E Glover; Melanie Scully; Colm B Collins; Brittelle E Bowers; Eric L Campbell; Sean P Colgan Journal: J Immunol Date: 2011-04-22 Impact factor: 5.422
Authors: Simon A Hirota; Kyla Fines; Jeffrey Ng; Danya Traboulsi; Josh Lee; Eikichi Ihara; Yan Li; William G Willmore; Daniel Chung; Melanie M Scully; Thomas Louie; Shaun Medlicott; Manigandan Lejeune; Kris Chadee; Glen Armstrong; Sean P Colgan; Daniel A Muruve; Justin A MacDonald; Paul L Beck Journal: Gastroenterology Date: 2010-03-27 Impact factor: 22.682
Authors: Louise E Glover; Karina Irizarry; Melanie Scully; Eric L Campbell; Brittelle E Bowers; Carol M Aherne; Douglas J Kominsky; Christopher F MacManus; Sean P Colgan Journal: J Immunol Date: 2011-01-03 Impact factor: 5.422