Gastroenterology

Gastroenterology

Volume 134, Issue 1, January 2008, Pages 156-165.e1
Gastroenterology

Basic–Alimentary Tract
The Hydroxylase Inhibitor Dimethyloxalylglycine Is Protective in a Murine Model of Colitis

https://doi.org/10.1053/j.gastro.2007.10.012Get rights and content

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.

Section snippets

Animals

Female C57BL/6 strain mice were bred under specific pathogen-free conditions at the BioResources Unit (Trinity College, Dublin, Ireland). Mice were fed an irradiated diet and housed on irradiated bedding and kept in individually ventilated and filtered cages (Tecniplast, Northants, UK). All animal experiments were performed in compliance with Irish Department of Health and Children regulations and approved by the Trinity College Bioresources ethical review board.

DMOG Treatment

DMOG (Caymen Chemicals, Ann

DMOG Activates NF-κB and HIF-1 in Cultured Intestinal Epithelial Cells

Initially, we investigated the presence of a functionally intact, oxygen-sensing system in cultured enterocytes. Consistent with reports in other cell types, exposure of Caco-2 (colon-derived epithelial) cells to hypoxia resulted in activation of the NF-κB pathway as reflected by the nuclear accumulation of p65 (Figure 1A) and phosphorylation of IKKα/β (Figure 1B). These cells also showed robust activation of the HIF-1 pathway in response to hypoxia (Figure 1C, left). Treatment of the Caco-2

Discussion

In this study we showed that the pan-hydroxylase inhibitor DMOG significantly ameliorates the severity of disease and accelerates recovery in a mouse model of UC. The symptoms of IBD can range from mild inflammation and discomfort to overt ulcerative disease requiring surgical treatment. The current therapeutic repertoire for IBD is significantly limited, with most advances being in the area of immunotherapy with monoclonal antibodies directed against inflammatory mediators such as TNF-α.29 A

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    Supported by grants from the Science Foundation Ireland, the Wellcome Trust, the Health Research Board of Ireland, and the Irish Higher Education Authority Programme for Research in Third Level Institutions. We thank Brian Cloak for imaging expertise.

    1

    E.P.C., P.G.F., and C.T.T. contributed equally to this study.

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