Interleukin-22 drives nitric oxide-dependent DNA damage and dysplasia in a murine model of colitis-associated cancer

被引：60

作者：

Wang, C. ^{[1
]}

Gong, G. ^{[2
]}

Sheh, A. ^{[1
]}

Muthupalani, S. ^{[1
]}

Bryant, E. M. ^{[1
]}

Puglisi, D. A. ^{[1
]}

Holcombe, H. ^{[1
]}

Conaway, E. A. ^{[3
]}

Parry, N. A. P. ^{[1
]}

Bakthavatchalu, V. ^{[1
]}

Short, S. P. ^{[4
,5
]}

Williams, C. S. ^{[4
,5
]}

Wogan, G. N. ^{[2
]}

Tannenbaum, S. R. ^{[2
]}

Fox, J. G. ^{[1
,2
]}

Horwitz, B. H. ^{[3
]}

机构：

[1] MIT, Div Comparat Med, Cambridge, MA 02139 USA

[2] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[3] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA

[4] Vanderbilt Univ, Sch Med, Dept Med, Div Gastroenterol Hepatol & Nutr, Nashville, TN 37212 USA

[5] Vanderbilt Univ, Sch Med, Dept Canc Biol, Nashville, TN 37212 USA

来源：

MUCOSAL IMMUNOLOGY | 2017年 / 10卷 / 06期

关键词：

HELICOBACTER-HEPATICUS; ULCERATIVE-COLITIS; COLON-CANCER; RAG2-DEFICIENT MICE; COLORECTAL-CANCER; CROHNS-DISEASE; INFLAMMATION; CARCINOGENESIS; SYNTHASE; CELLS;

D O I：

10.1038/mi.2017.9

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

071005 [微生物学]; 100108 [医学免疫学];

摘要：

The risk of colon cancer is increased in patients with Crohn's disease and ulcerative colitis. Inflammation-induced DNA damage could be an important link between inflammation and cancer, although the pathways that link inflammation and DNA damage are incompletely defined. RAG2-deficient mice infected with Helicobacter hepaticus (Hh) develop colitis that progresses to lower bowel cancer. This process depends on nitric oxide (NO), a molecule with known mutagenic potential. We have previously hypothesized that production of NO by macrophages could be essential for Hh-driven carcinogenesis, however, whether Hh infection induces DNA damage in this model and whether this depends on NO has not been determined. Here we demonstrate that Hh infection of RAG2-deficient mice rapidly induces expression of iNOS and the development of DNA double-stranded breaks (DSBs) specifically in proliferating crypt epithelial cells. Generation of DSBs depended on iNOS activity, and further, induction of iNOS, the generation of DSBs, and the subsequent development of dysplasia were inhibited by depletion of the Hh-induced cytokine IL-22. These results demonstrate a strong association between Hh-induced DNA damage and the development of dysplasia, and further suggest that IL-22-dependent induction of iNOS within crypt epithelial cells rather than macrophages is a driving force in this process.

引用

页码：1504 / 1517

页数：14

共 41 条

[1]

Ahn B, 2001, CANCER RES, V61, P8357

[2]

Gut microbiome compositional and functional differences between tumor and non-tumor adjacent tissues from cohorts from the US and Spain [J].