RRC ID 18108
Author Tu SP, Quante M, Bhagat G, Takaishi S, Cui G, Yang XD, Muthuplani S, Shibata W, Fox JG, Pritchard DM, Wang TC.
Title IFN-γ inhibits gastric carcinogenesis by inducing epithelial cell autophagy and T-cell apoptosis.
Journal Cancer Res.
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.
Volume 71(12)
Pages 4247-59
Published 2011-6-15
DOI 10.1158/0008-5472.CAN-10-4009
PII 0008-5472.CAN-10-4009
PMID 21512143
PMC PMC3139967
MeSH Animals Apoptosis* Apoptosis Regulatory Proteins / physiology 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
IF 9.13
Times Cited 52
Human and Animal Cells MKN28 (RCB1000)