Nitric oxide and TNF-alpha trigger colonic inflammation and carcinogenesis in Helicobacter hepaticus-infected, Rag2-deficient mice.
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.
Erdman
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Division of Comparative Medicine, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. serdman@mit.edu
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Poutahidis
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Jackson
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Schauer
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Wogan
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D000818:Animals; D001120:Arginine / Q000494:pharmacology; D003106:Colon / Q000201:enzymology / Q000276:immunology / Q000382:microbiology / Q000473:pathology*; D003110:Colonic Neoplasms / Q000150:complications / Q000276:immunology / Q000382:microbiology / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016481:Helicobacter Infections / Q000201:enzymology / Q000276:immunology / Q000382:microbiology* / Q000652:urine; D044923:Helicobacter hepaticus / Q000276:immunology*; D007249:Inflammation / Q000276:immunology / Q000382:microbiology; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D009566:Nitrates / Q000652:urine; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D009566:Nitrates; C499308:Rag2 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D001120:Arginine; D052247:Nitric Oxide Synthase Type II