title: The hydroxylase inhibitor dimethyloxalylglycine is protective in a murine model of colitis.
abstract: 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.
authors.affiliation: UCD Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Eoin P
authors.initials: EP
authors.lastname: Cummins
authors.forename: Fergal
authors.initials: F
authors.lastname: Seeballuck
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Keely
authors.forename: Niamh E
authors.initials: NE
authors.lastname: Mangan
authors.forename: John J
authors.initials: JJ
authors.lastname: Callanan
authors.forename: Padraic G
authors.initials: PG
authors.lastname: Fallon
authors.forename: Cormac T
authors.initials: CT
authors.lastname: Taylor
mesh_terms: 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
chemical_list: D000600:Amino Acids, Dicarboxylic; D004791:Enzyme Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D006899:Mixed Function Oxygenases; C040947:oxalylglycine