Nitric oxide and TNF-α trigger colonic inflammation and carcinogenesis in Helicobacter hepaticus-infected, Rag2-deficient mice
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.; Tannenbaum, Steven Robert; Fox, James G.; ... Show more Show less
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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.
DepartmentMassachusetts Institute of Technology. Department of Biological Engineering; Massachusetts Institute of Technology. Division of Comparative Medicine
Proceedings of the National Academy of Sciences
National Academy of Sciences (U.S.)
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.
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