Nitric oxide and TNF-α trigger colonic inflammation and carcinogenesis in Helicobacter hepaticus-infected, Rag2-deficient mice

被引：153

作者：

Erdman, S. E. ^{[1
]}

Rao, V. P. ^{[1
]}

Poutahidis, T. ^{[1
,3
]}

Rogers, A. B. ^{[1
]}

Taylor, C. L. ^{[1
]}

Jackson, E. A. ^{[1
]}

Ge, Z. ^{[1
]}

Lee, C. W. ^{[1
]}

Schauer, D. B. ^{[1
,2
]}

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

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

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

机构：

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

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

[3] Aristotle Univ Thessaloniki, Fac Vet Med, Pathol Lab, GR-54006 Thessaloniki, Greece

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2009年 / 106卷 / 04期

基金：

美国国家卫生研究院;

关键词：

colorectal cancer; IBD; innate immunity; REGULATORY T-CELLS; NF-KAPPA-B; ULCERATIVE-COLITIS; BOWEL-DISEASE; MOUSE MODEL; LIPID-PEROXIDATION; SYNTHASE ACTIVITY; NITROGEN-DIOXIDE; APC(MIN/+) MICE; IL-10(-/-) MICE;

D O I：

10.1073/pnas.0812347106

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Recombinase-activating gene-2-deficient (Rag2(-/-)) mice lacking functional lymphocytes provide a useful model of chronic inflammatory bowel disease-emulating events in human colon cancer. Infection of Rag2(-/-) mice with Helicobacter hepaticus led to accumulation of macrophages and neutrophils in the colon, a process temporally related to up-regulation of tissue inducible nitric oxide synthase ( iNOS) expression at the site of infection and increased nitric oxide ( NO) production, as evidenced by urinary excretion of nitrate. Progressive development of increasingly severe inflammation, hyperplasia, dysplasia, and cancer accompanied these changes. Concurrent administration of an iNOS inhibitor prevented NO production and abrogated epithelial pathology and inhibited the onset of cancer. The presence of Gr-(1+) neutrophils and elevated tumor necrosis factor-alpha (TNF-alpha) expression in colon were required for increased iNOS expression and cancer, whereas interleukin-10 (IL-10) down-regulated TNF-alpha and iNOS expression and suppressed cancer. Anti-inflammatory CD4(+) regulatory lymphocytes also down-regulated iNOS and reduced cancer formation. Collectively, these results confirm essential roles for inflammation, increased TNF-alpha expression, and elevated NO production in colon carcinogenesis.

引用

页码：1027 / 1032

页数：6

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