Tumor and Stem Cell Biology IFN-g Inhibits Gastric Carcinogenesis by Inducing Epithelial Cell Autophagy and T-Cell Apoptosis

IFN-g 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 Hþ/Kþ-ATPase-IFN-g transgenic mouse that overexpresses murine IFN-g in the stomach mucosa. In contrast to the expected proinflammatory role during infection, we found that IFN-g overexpression failed to induce gastritis and instead inhibited gastric carcinogenesis induced by interleukin-1beta (IL-1b) and/ or Helicobacter infection. Helper T cell (Th) 1 and Th17 immune responses were inhibited by IFN-g through Fas induction and apoptosis in CD4 T cells. IFN-g also induced autophagy in gastric epithelial cells through increased expression of Beclin-1. Finally, in the gastric epithelium, IFN-g also inhibited IL-1band Helicobacterinduced epithelial apoptosis, proliferation, and Dckl1þ cell expansion. Taken together, our results suggest that IFN-g 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. Cancer Res; 71(12); 4247–59. 2011 AACR.