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

S E Erdman1, V P Rao, T Poutahidis

  • 1Division of Comparative Medicine, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. serdman@mit.edu

Proceedings of the National Academy of Sciences of the United States of America
|January 24, 2009
PubMed

Insights

Recombinase-activating gene-2-deficient mice infected with Helicobacter hepaticus developed colon cancer. Inhibiting inducible nitric oxide synthase (iNOS) prevented cancer, highlighting NO

Area of Science:

  • Immunology
  • Gastroenterology
  • Oncology

Background:

  • Recombinase-activating gene-2-deficient (Rag2(-/-)) mice are a model for chronic inflammatory bowel disease and colon cancer.
  • Helicobacter hepaticus infection in Rag2(-/-) mice mimics human colon cancer development.

Purpose of the Study:

  • To investigate the role of inducible nitric oxide synthase (iNOS) and associated inflammatory mediators in Helicobacter hepaticus-induced colon carcinogenesis in Rag2(-/-) mice.
  • To explore the impact of neutrophils, tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10), and regulatory T cells on iNOS expression and cancer development.

Main Methods:

  • Infection of Rag2(-/-) mice with Helicobacter hepaticus.
  • Assessment of inflammatory cell accumulation (macrophages, neutrophils).
  • Measurement of inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production (urinary nitrate excretion).
  • Evaluation of epithelial pathology (hyperplasia, dysplasia) and cancer incidence.
  • Administration of an iNOS inhibitor.
  • Analysis of Gr-1(+) neutrophils, TNF-alpha, IL-10, and CD4(+) regulatory T cell involvement.

Main Results:

  • Helicobacter hepaticus infection induced macrophage and neutrophil accumulation, increased iNOS expression, and elevated NO production in the colon.
  • Progressive inflammation, hyperplasia, dysplasia, and cancer developed in infected mice.
  • iNOS inhibition abrogated NO production, prevented epithelial pathology, and inhibited cancer onset.
  • Neutrophils and TNF-alpha were required for increased iNOS expression and cancer.
  • IL-10 and CD4(+) regulatory T cells suppressed TNF-alpha and iNOS expression, reducing cancer formation.

Conclusions:

  • Inflammation, elevated TNF-alpha, and increased NO production are critical drivers of colon carcinogenesis in this model.
  • Targeting iNOS and modulating inflammatory pathways holds therapeutic potential for colon cancer prevention.

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