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


RESULTS
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.


CONCLUSIONS
The findings indicate that, in this model of ulcerative colitis, Mutyh plays a major role in maintaining intestinal integrity by affecting the inflammatory response.
Casorelli
Ida
I
Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Rome, Italy. ida.casorelli@ospedalesantandrea.it
Pannellini
Tania
T
De Luca
Gabriele
G
Degan
Paolo
P
Chiera
Federica
F
Iavarone
Ivano
I
Giuliani
Alessandro
A
Butera
Alessia
A
Boirivant
Monica
M
Musiani
Piero
P
Bignami
Margherita
M
D000818:Animals; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism*; D004247:DNA / Q000235:genetics / Q000378:metabolism; D045647:DNA Glycosylases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D004260:DNA Repair; D016264:Dextran Sulfate / Q000494:pharmacology; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D051379:Mice; D053842:Microsatellite Instability / Q000187:drug effects; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects
D004247:DNA; D016264:Dextran Sulfate; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase