The hydroxylase inhibitor dimethyloxalylglycine is protective in a murine model of colitis.
OBJECTIVE
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.
Cummins
Eoin P
EP
UCD Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
Seeballuck
Fergal
F
Keely
Stephen J
SJ
Mangan
Niamh E
NE
Callanan
John J
JJ
Fallon
Padraic G
PG
Taylor
Cormac T
CT
D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D018938:Caco-2 Cells / Q000187:drug effects / Q000378:metabolism; D018929:Cell Culture Techniques; D003092:Colitis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D016328:NF-kappa B / Q000378:metabolism
D000600:Amino Acids, Dicarboxylic; D004791:Enzyme Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D006899:Mixed Function Oxygenases; C040947:oxalylglycine