title: IFN-γ inhibits gastric carcinogenesis by inducing epithelial cell autophagy and T-cell apoptosis.
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.
authors.affiliation: Department of Medicine, College of Physicians & Surgeons, Columbia University, New York, USA.
authors.forename: Shui Ping
authors.initials: SP
authors.lastname: Tu
authors.forename: Michael
authors.initials: M
authors.lastname: Quante
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.forename: Shigeo
authors.initials: S
authors.lastname: Takaishi
authors.forename: Guanglin
authors.initials: G
authors.lastname: Cui
authors.forename: Xiang Dong
authors.initials: XD
authors.lastname: Yang
authors.forename: Sureshkumar
authors.initials: S
authors.lastname: Muthuplani
authors.forename: Wataru
authors.initials: W
authors.lastname: Shibata
authors.forename: James G
authors.initials: JG
authors.lastname: Fox
authors.forename: D Mark
authors.initials: DM
authors.lastname: Pritchard
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D001343:Autophagy; D000071186:Beclin-1; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000089742:Doublecortin-Like Kinases; D005753:Gastric Mucosa / Q000473:pathology; D005756:Gastritis / Q000209:etiology; D017506:H(+)-K(+)-Exchanging ATPase / Q000502:physiology; D016481:Helicobacter Infections / Q000150:complications*; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology*; D053583:Interleukin-1beta / Q000502:physiology; D008679:Metaplasia; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000032:analysis; D013274:Stomach Neoplasms / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D013601:T-Lymphocytes / Q000502:physiology*; D058504:Th17 Cells / Q000276:immunology
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D053583:Interleukin-1beta; D007371:Interferon-gamma; D000089742:Doublecortin-Like Kinases; C485525:Dclk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D017506:H(+)-K(+)-Exchanging ATPase