The hydroxylase inhibitor dimethyloxalylglycine is protective in a murine model of colitis
EP Cummins, F Seeballuck, SJ Keely, NE Mangan… - Gastroenterology, 2008 - Elsevier
Gastroenterology, 2008•Elsevier
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 …
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 …
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 a hydroxylase inhibitor dimethyloxalylglycine (DMOG) on Caco-2 intestinal epithelial cells in vitro (Caco-2) 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.
Elsevier