Inducible nitric oxide synthase-dependent DNA damage in mouse model of inflammatory bowel disease.
Increased cancer risk occurs in inflammatory bowel disease (IBD) undergoing long-term chronic inflammation. To evaluate whether inducible nitric oxide synthase (iNOS)-dependent DNA damage plays a role in the carcinogenic process triggered by IBD, we prepared a mouse model of IBD induced by transfer of CD45RBhighCD4+ T cells lacking regulatory T cells to female severe combined immunodeficiency (SCID) mice. CD45RBhighCD4+ T cells were isolated from mouse spleen after staining with fluorescein isothiocyanate (FITC)-conjugated anti-CD45RB monoclonal antibody, followed by anti-FITC-conjugated microbeads. This IBD mouse model showed that the bodyweight increased with aging to a lesser extent than non-treated controls, and that the intestine was shortened. Pathological findings of this mouse model, which showed severe inflammation in colon tissues, were similar to IBD patients. Double immunofluorescence technique revealed that both 8-nitroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) were formed mainly in epithelial cells of the IBD mouse model. 8-Nitroguanine was formed in most of 8-oxodG-immunoreactive nuclei of epithelial cells. iNOS, proliferating cell nuclear antigen and p53 protein were also expressed in the colon epithelium. These results indicate that nitrative DNA damage, as well as oxidative DNA damage, is induced in colon epithelial cells of the IBD mouse model followed by proliferation of these cells, which may contribute to colon carcinogenesis.
Ding
Xiaohui
X
Department of Anatomy, Mie University School of Medicine, Tsu, Mie 514-8507, Japan.
Hiraku
Yusuke
Y
Ma
Ning
N
Kato
Takuma
T
Saito
Kanako
K
Nagahama
Masato
M
Semba
Reiji
R
Kuribayashi
Kagemasa
K
Kawanishi
Shosuke
S
D000375:Aging; D000818:Animals; D001835:Body Weight; D015496:CD4-Positive T-Lymphocytes; D049109:Cell Proliferation; D002908:Chronic Disease; D003110:Colonic Neoplasms / Q000276:immunology* / Q000503:physiopathology*; D004249:DNA Damage; D004195:Disease Models, Animal; D005260:Female; D007150:Immunohistochemistry; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000503:physiopathology*; D051379:Mice; D016513:Mice, SCID; D019001:Nitric Oxide Synthase / Q000494:pharmacology*; D018384:Oxidative Stress
D019001:Nitric Oxide Synthase