Loss of prolyl hydroxylase-1 protects against colitis through reduced epithelial cell apoptosis and increased barrier function
Citation:Murtaza M. Tambuwala, Eoin P. Cummins, Colin R. Lenihan, Judith Kiss, Markus Stauch, Carsten C. Scholz, Peter Fraisl, Felix Lasitschka, Martin Mollenhauer, Sean P. Saunders, Patrick H. Maxwell, Peter Carmeliet, Padraic G. Fallon, Martin Schneider, Cormac T. Taylor, Loss of prolyl hydroxylase-1 protects against colitis through reduced epithelial cell apoptosis and increased barrier function, Gastroenterology, 139, 6, 2010, 2093-2101
Loss of prolyl hydroxylase-1 protects against colitis through reduced epithelial cell apoptosis and increased barrier function.pdf (Published (author's copy) - Peer Reviewed) 759.0Kb
Background and Aims: HIF prolyl hydroxylase inhibitors are protective in mouse models of inflammatory bowel disease (IBD). Here, we investigated the therapeutic target(s) and mechanism(s) involved. Methods: The effect of genetic deletion of individual HIF-prolyl hydroxylase enzymes (PHD) on the development of dextran sulphate sodium (DSS)-induced colitis was examined in mice. Results: PHD1-/-, but not PHD2+/- or PHD3-/-, mice were less susceptible to the development of colitis than wild type controls as determined by weight loss, disease activity, colon histology, neutrophil infiltration and cytokine expression. Reduced susceptibility of PHD1-/- mice to colitis was associated with increased density of colonic epithelial cells relative to wild type controls which was due to decreased levels of apoptosis resulting in enhanced epithelial barrier function. Furthermore, using cultured epithelial cells it was confirmed that hydroxylase inhibition reversed DSS-induced apoptosis and barrier dysfunction. Finally, PHD1 levels were increased with disease severity in intestinal tissue from IBD patients and in colonic tissues from DSS treated mice. Conclusions: These results imply a role for PHD1 as a positive regulator of intestinal epithelial cell apoptosis in the inflamed colon. Genetic loss of PHD1 is protective against colitis through decreased epithelial cell apoptosis and consequent enhancement of intestinal epithelial barrier function. Thus, targeted PHD1 inhibition may represent a new therapeutic approach in IBD.
Science Foundation Ireland (SFI)
Type of material:Journal Article
Availability:Full text available
Subject (TCD):Immunology, Inflammation & Infection