IFN-γ inhibits gastric carcinogenesis by inducing epithelial cell autophagy and T-cell apoptosis

Cancer Res. 2011 Jun 15;71(12):4247-59. doi: 10.1158/0008-5472.CAN-10-4009. Epub 2011 Apr 21.

Abstract

IFN-γ mediates responses to bacterial infection and autoimmune disease, but it is also an important tumor suppressor. It is upregulated in the gastric mucosa by chronic Helicobacter infection; however, whether it plays a positive or negative role in inflammation-associated gastric carcinogenesis is unexplored. To study this question, we generated an H(+)/K(+)-ATPase-IFN-γ transgenic mouse that overexpresses murine IFN-γ in the stomach mucosa. In contrast to the expected proinflammatory role during infection, we found that IFN-γ overexpression failed to induce gastritis and instead inhibited gastric carcinogenesis induced by interleukin-1beta (IL-1β) and/or Helicobacter infection. Helper T cell (Th) 1 and Th17 immune responses were inhibited by IFN-γ through Fas induction and apoptosis in CD4 T cells. IFN-γ also induced autophagy in gastric epithelial cells through increased expression of Beclin-1. Finally, in the gastric epithelium, IFN-γ also inhibited IL-1β- and Helicobacter-induced epithelial apoptosis, proliferation, and Dckl1(+) cell expansion. Taken together, our results suggest that IFN-γ coordinately inhibits bacterial infection and carcinogenesis in the gastric mucosa by suppressing putative gastric progenitor cell expansion and reducing epithelial cell apoptosis via induction of an autophagic program.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / physiology
  • Apoptosis*
  • Autophagy*
  • Beclin-1
  • Cell Line, Tumor
  • Cell Proliferation
  • Gastric Mucosa / pathology
  • Gastritis / etiology
  • H(+)-K(+)-Exchanging ATPase / physiology
  • Helicobacter Infections / complications*
  • Humans
  • Interferon-gamma / physiology*
  • Interleukin-1beta / physiology
  • Metaplasia
  • Mice
  • Protein-Serine-Threonine Kinases / analysis
  • Stomach Neoplasms / etiology
  • Stomach Neoplasms / pathology
  • Stomach Neoplasms / prevention & control*
  • T-Lymphocytes / physiology*
  • Th17 Cells / immunology

Substances

  • Apoptosis Regulatory Proteins
  • Beclin-1
  • Becn1 protein, mouse
  • Interleukin-1beta
  • Interferon-gamma
  • Dclk1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • H(+)-K(+)-Exchanging ATPase