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...
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| Veröffentlicht in: | Gastroenterology (New York, N.Y. 1943) N.Y. 1943), 2008, Vol.134 (1), p.156-165.e1 |
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| container_title | Gastroenterology (New York, N.Y. 1943) |
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| creator | Cummins, Eoin P Seeballuck, Fergal Keely, Stephen J Mangan, Niamh E Callanan, John J Fallon, Padraic G Taylor, Cormac T |
| description | 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. |
| doi_str_mv | 10.1053/j.gastro.2007.10.012 |
| format | Article |
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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. 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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. 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| subjects | Amino Acids, Dicarboxylic - pharmacology Amino Acids, Dicarboxylic - therapeutic use Animals Caco-2 Cells - drug effects Caco-2 Cells - metabolism Cell Culture Techniques Colitis - metabolism Colitis - pathology Colitis - prevention & control Disease Models, Animal Enzyme Inhibitors - pharmacology Enzyme Inhibitors - therapeutic use Female Gastroenterology and Hepatology Humans Hypoxia-Inducible Factor 1, alpha Subunit - metabolism Mice Mice, Inbred C57BL Mixed Function Oxygenases - antagonists & inhibitors NF-kappa B - metabolism |
| title | The Hydroxylase Inhibitor Dimethyloxalylglycine Is Protective in a Murine Model of Colitis |
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