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

• Main Authors: Tu, Shui Ping (Author), Quante, Michael (Author), Bhagat, Govind (Author), Takaishi, Shigeo (Author), Cui, Guanglin (Author), Yang, Xiang Dong (Author), Muthupalani, Sureshkumar (Contributor), Shibata, Wataru (Author), Fox, James G. (Contributor), Pritchard, D. Mark (Author), Wang, Timothy C. (Author)
• Other Authors: Massachusetts Institute of Technology. Department of Biological Engineering (Contributor), Massachusetts Institute of Technology. Division of Comparative Medicine (Contributor)
• Format: Article
• Language: English
• Published: American Association for Cancer Research, 2012-12-12T20:53:28Z.
• Subjects: Article
• Online Access: Get fulltext

Author Manuscript 2012 June 15.
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[superscript +]/K[superscript +]-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[superscript +] 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. Cancer Res; 71(12); 4247-59.