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Gastroenterology. 2008 Jan;134(1):156-65. doi: 10.1053/j.gastro.2007.10.012. Epub 2007 Oct 10.

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

Author information

1
UCD Conway Institute, University College Dublin, Belfield, Dublin, Ireland.

Abstract

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.

PMID:
18166353
DOI:
10.1053/j.gastro.2007.10.012
[Indexed for MEDLINE]

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