The Mutyh base excision repair gene influences the inflammatory response in a mouse model of ulcerative colitis

• Published in: PloS one 2010-08, Vol.5 (8), p.e12070
• Main Authors: Casorelli, Ida, Pannellini, Tania, De Luca, Gabriele, Degan, Paolo, Chiera, Federica, Iavarone, Ivano, Giuliani, Alessandro, Butera, Alessia, Boirivant, Monica, Musiani, Piero, Bignami, Margherita
• Format: Article
• Language: English
• Subjects: 8-Hydroxyguanine; Animals; Base excision repair; Cancer; Cell Biology; Colitis, Ulcerative - chemically induced; Colitis, Ulcerative - genetics; Colitis, Ulcerative - metabolism; Colon; Colorectal cancer; Colorectal carcinoma; Comparative analysis; Cytokines; Deoxyribonucleic acid; Dextran; Dextran sulfate; Dextran Sulfate - pharmacology; Dextrans; Disease Models, Animal; Disease prevention; DNA; DNA - genetics; DNA - metabolism; DNA glycosylase; DNA Glycosylases - deficiency; DNA Glycosylases - genetics; DNA Glycosylases - metabolism; DNA Repair; Familial adenomatous polyposis; Foxp3 protein; Gastroenterology and Hepatology/Inflammatory Bowel Disease; Gene expression; Gene Expression Profiling; Genes; Genetic aspects; Genomes; Health aspects; Health risks; Human behavior; Hyperplasia; Immunoregulation; Inflammation; Inflammatory bowel disease; Inflammatory bowel diseases; Inflammatory response; Intestine; Lesions; Lymphocytes; Lymphocytes T; Mice; Microsatellite instability; Microsatellite Instability - drug effects; Microscopy; Molecular Biology/DNA Repair; Mutation; Oxidation-Reduction; Oxidative stress; Oxidative Stress - drug effects; Proteins; Repair; Rodents; Sodium; Stability; Stability analysis; Sulfate; Sulfates; T cells; Tumors; Ulcerative colitis
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0012070

The Mutyh DNA glycosylase is involved in the repair of oxidized DNA bases. Mutations in the human MUTYH gene are responsible for colorectal cancer in familial adenomatous polyposis. Since defective DNA repair genes might contribute to the increased cancer risk associated with inflammatory bowel diseases, we compared the inflammatory response of wild-type and Mutyh(-/-) mice to oxidative stress. The severity of colitis, changes in expression of genes involved in DNA repair and inflammation, DNA 8-oxoguanine levels and microsatellite instability were analysed in colon of mice treated with dextran sulfate sodium (DSS). The Mutyh(-/-) phenotype was associated with a significant accumulation of 8-oxoguanine in colon DNA of treated mice. A single DSS cycle induced severe acute ulcerative colitis in wild-type mice, whereas lesions were modest in Mutyh(-/-) mice, and this was associated with moderate variations in the expression of several cytokines. Eight DSS cycles caused chronic colitis in both wild-type and Mutyh(-/-) mice. Lymphoid hyperplasia and a significant reduction in Foxp3(+) regulatory T cells were observed only in Mutyh(-/-) mice. The findings indicate that, in this model of ulcerative colitis, Mutyh plays a major role in maintaining intestinal integrity by affecting the inflammatory response.