Basic–Alimentary TractThe Hydroxylase Inhibitor Dimethyloxalylglycine Is Protective in a Murine Model of Colitis
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
References (38)
- et al.
Autocrine regulation of epithelial permeability by hypoxia: role for polarized release of tumor necrosis factor alpha
Gastroenterology
(1998) - et al.
Signalling hypoxia by HIF hydroxylases
Biochem Biophys Res Commun
(2005) - et al.
IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer
Cell
(2004) - et al.
A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice
Gastroenterology
(1990) - et al.
Concordant regulation of gene expression by hypoxia and 2-oxoglutarate-dependent dioxygenase inhibition: the role of HIF-1alpha, HIF-2alpha, and other pathways
J Biol Chem
(2006) - et al.
The role of HIF-1alpha in myeloid cell inflammation
Trends Immunol
(2005) Control of B lymphocyte apoptosis by the transcription factor NF-kappaB
Immunity
(2006)- et al.
Cox-2 is regulated by Toll-like receptor-4 (TLR4) signaling: role in proliferation and apoptosis in the intestine
Gastroenterology
(2006) - et al.
Regional manifestations and control of the immune system
FASEB J
(2002) Mechanisms of disease: pathogenesis of Crohn’s disease and ulcerative colitis
Nat Clin Pract Gastroenterol Hepatol
(2006)
The fundamental basis of inflammatory bowel disease
J Clin Invest
Proline hydroxylation and gene expression
Annu Rev Biochem
Asparagine hydroxylation of the HIF transactivation domain: a hypoxic switch
Science
Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity
Proc Natl Acad Sci U S A
Posttranslational hydroxylation of ankyrin repeats in IkappaB proteins by the hypoxia-inducible factor (HIF) asparaginyl hydroxylase, factor inhibiting HIF (FIH)
Proc Natl Acad Sci U S A
Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis
J Clin Invest
The two faces of IKK and NF-kappaB inhibition: prevention of systemic inflammation but increased local injury following intestinal ischemia-reperfusion
Nat Med
IkappaB-kinase beta-dependent NF-kappaB activation provides radioprotection to the intestinal epithelium
Proc Natl Acad Sci U S A
Epithelial-cell-intrinsic IKK-beta expression regulates intestinal immune homeostasis
Nature
Cited by (338)
Fundamental role for the creatine kinase pathway in protection from murine colitis
2023, Mucosal ImmunologySUMOylation indirectly suppresses activity of the HIF-1α pathway in intestinal epithelial cells
2023, Journal of Biological ChemistryHypoxia Primes Human ISCs for Interleukin-Dependent Rescue of Stem Cell Activity
2023, Cellular and Molecular Gastroenterology and Hepatology
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.