The Mutyh Base Excision Repair Gene Influences the Inflammatory Response in a Mouse Model of Ulcerative Colitis |
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Authors: | Ida Casorelli Tania Pannellini Gabriele De Luca Paolo Degan Federica Chiera Ivano Iavarone Alessandro Giuliani Alessia Butera Monica Boirivant Piero Musiani Margherita Bignami |
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Affiliation: | 1. Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Rome, Italy.; 2. Aging Research Center, Gabriele D''Annunzio University of Chieti, Chieti, Italy.; 3. Istituto Tumori di Genova, Genova, Italy.; 4. Department of Infectious Parasitic and Immuno-mediated Diseases, Istituto Superiore di Sanità, Rome, Italy.;Emory Unviersity, United States of America |
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Abstract: | BackgroundThe 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.Methodology/Principal FindingsThe 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−/− phenotpe 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.ConclusionsThe findings indicate that, in this model of ulcerative colitis, Mutyh plays a major role in maintaining intestinal integrity by affecting the inflammatory response. |
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