Nitric oxide and TNF-α trigger colonic inflammation and carcinogenesis in Helicobacter hepaticus-infected, Rag2-deficient mice
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Tannenbaum_Nitric oxide.pdf
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Author(s)
Rao, V. P.
Poutahidis, T.
Rogers, A. B.
Taylor, C. L.
Jackson, E. A.
Lee, C. W.
Schauer, D. B.
Erdman, Susan E.
Ge, Zhongming
Wogan, Gerald N.
Date Issued
January 2009
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences (U.S.)
Citation
Erdman, S. E., V. P. Rao, T. Poutahidis, A. B. Rogers, C. L. Taylor, E. A. Jackson, Z. Ge, et al. “Nitric Oxide and TNF- Trigger Colonic Inflammation and Carcinogenesis in Helicobacter Hepaticus-Infected, Rag2-Deficient Mice.” Proceedings of the National Academy of Sciences 106, no. 4 (January 21, 2009): 1027–1032.
Version
Final published version
Abstract
Recombinase-activating gene-2-deficient (Rag2[superscript −/−]) mice lacking functional lymphocytes provide a useful model of chronic inflammatory bowel disease-emulating events in human colon cancer. Infection of Rag2[superscript −/−] 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[superscript +] neutrophils and elevated tumor necrosis factor-α (TNF-α) expression in colon were required for increased iNOS expression and cancer, whereas interleukin-10 (IL-10) down-regulated TNF-α and iNOS expression and suppressed cancer. Anti-inflammatory CD4[superscript +] regulatory lymphocytes also down-regulated iNOS and reduced cancer formation. Collectively, these results confirm essential roles for inflammation, increased TNF-α expression, and elevated NO production in colon carcinogenesis.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Division of Comparative Medicine
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DOI of Published Version
https://doi.org/10.1073/pnas.0812347106
