Open AccessInducible nitric oxide synthase‐dependent DNA damage in mouse model of inflammatory bowel disease
Author(s) -
Ding Xiaohui,
Hiraku Yusuke,
Ma Ning,
Kato Takuma,
Saito Kanako,
Nagahama Masato,
Semba Reiji,
Kuribayashi Kagemasa,
Kawanishi Shosuke
Publication year - 2005
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2005.00024.x
Subject(s) - inflammatory bowel disease , nitric oxide synthase , inflammation , fluorescein isothiocyanate , dna damage , pathology , microbiology and biotechnology , biology , immunology , spleen , proliferating cell nuclear antigen , cancer research , nitric oxide , medicine , immunohistochemistry , dna , endocrinology , biochemistry , disease , physics , quantum mechanics , fluorescence
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 CD45RB high CD4 + T cells lacking regulatory T cells to female severe combined immunodeficiency (SCID) mice. CD45RB high CD4 + 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. ( Cancer Sci 2005; 96: 157–163)