Nitric oxide and TNF-alpha trigger colonic inflammation and carcinogenesis in Helicobacter hepaticus-infected, Rag2-deficient mice - PubMed (original) (raw)

. 2009 Jan 27;106(4):1027-32.

doi: 10.1073/pnas.0812347106. Epub 2009 Jan 21.

V P Rao, T Poutahidis, A B Rogers, C L Taylor, E A Jackson, Z Ge, C W Lee, D B Schauer, G N Wogan, S R Tannenbaum, J G Fox

Affiliations

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

S E Erdman et al. Proc Natl Acad Sci U S A. 2009.

Abstract

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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

Urinary nitrate excretion after infection with H. hepaticus. (A) Temporal increase in urinary nitrate excretion followed infection with H. hepaticus. (B) Nitrate excretion was elevated in infected _Rag2_−/− mice with cancer but not WT mice without cancer. Treatment with NMA or TREG cells decreased urinary nitrate levels to that of uninfected _Rag2_−/− mice and prevented cancer development in infected _Rag2_−/− mice. (C) FIHC showed colocalization of F4/80 and iNOS proteins in the colon of an _H. hepaticus_-infected mouse. (Original magnification, 100×.) (D) Higher magnification (1,000×) of C reveals iNOS expression in inflammatory cells.

Fig. 2.

Fig. 2.

Modulation of expression of iNOS and inflammatory cytokines in colon tissue. (A) Expressions of proinflammatory cytokines and iNOS were significantly increased after infection with H. hepaticus (Hh). Depletion of Gr-1+ cells (B) and TNF-α (C) decreased iNOS expression. (D) Infected double-knockout mice showed significant increases in iNOS and IFN-γ gene expression. (E) TEFF cells increased levels of IFN (IFN-γ) and iNOS expression.

Fig. 3.

Fig. 3.

NO synthase inhibitor NMA inhibits development of malignancy in mice. (A) Numbers of 7/4+ neutrophils and F4/80+ macrophages were unchanged by NMA treatment; therefore, protective effects of NMA were not attributable to reduced numbers of inflammatory cells. (B) Histopathologic indices of dysplasia and cancer were reduced by NMA treatment.

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