Interferon-γ directly induces gastric epithelial cell death and is required for progression to metaplasia

J Pathol. 2019 Apr;247(4):513-523. doi: 10.1002/path.5214. Epub 2019 Jan 24.

Abstract

Chronic inflammation of the gastric mucosa, often caused by autoimmune gastritis and/or infection with Helicobacter pylori, can lead to atrophy of acid-secreting parietal cells with metaplasia of remaining cells. The histological pattern marks a critical step in the progression from chronic gastritis to gastric cancer, yet underlying mechanism(s) of inflammation-induced cell death of gastric epithelial cells are poorly understood. We investigated direct effects of a type 1 cytokine associated with autoimmunity and infection, interferon-γ (IFN-γ), on gastric epithelial cells. IFN-γ was applied to three-dimensional organoid cultures of gastric epithelial cells derived from gastric corpus gland (gastroids) of control and IFN-γ receptor-deficient mice. Gastroids were also treated with supernatants from activated immune cells isolated from a mouse model of autoimmune-mediated atrophic gastritis (TxA23) with and without IFN-γ expression. Finally, histopathological analysis of atrophy and metaplasia severity was performed in TxA23 mice and compared to TxA23 × Ifng-/- mice. Gastric epithelial cells in gastroid cultures expressed IFN-γ receptor in the basolateral membrane, and gastroids died when treated with IFN-γ in an IFN-γ receptor-dependent manner. Supernatants from immune cells containing high levels of IFN-γ were highly toxic to gastroids, and toxicity was tempered when IFN-γ was either neutralized using a monoclonal antibody or when supernatants from Ifng-/- mouse immune cells were used. Finally, TxA23 × Ifng-/- mice showed near-complete abrogation of pre-cancerous histopathological atrophy and metaplasia versus IFN-γ-sufficient controls. We identify IFN-γ as a critical promoter of parietal cell atrophy with metaplasia during the progression of gastritis to gastric atrophy and metaplasia. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: atrophic gastritis; inflammation; paligenosis; spasmolytic polypeptide-expressing metaplasia (SPEM).

Publication types

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

MeSH terms

  • Animals
  • Atrophy / pathology
  • Cell Death / physiology
  • Cell Transformation, Neoplastic / pathology
  • Disease Progression
  • Epithelial Cells / pathology
  • Gastric Mucosa / pathology*
  • Gastritis
  • Interferon-gamma / deficiency
  • Interferon-gamma / pharmacology
  • Interferon-gamma / physiology*
  • Metaplasia / pathology
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Parietal Cells, Gastric / pathology
  • Stomach Neoplasms / pathology*
  • Tumor Cells, Cultured

Substances

  • Interferon-gamma