Interferon-γ directly induces gastric epithelial cell death and is required for progression to metaplasia
| Autor: | Richard J. DiPaolo, Chun F Wong, Kevin A. Bockerstett, Jason C. Mills, Luciana H. Osaki, Blair B. Madison, Eric L. Ford |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
biology Autoimmune Gastritis Atrophic gastritis business.industry Chronic gastritis Helicobacter pylori medicine.disease biology.organism_classification Pathology and Forensic Medicine 03 medical and health sciences 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure 030220 oncology & carcinogenesis Metaplasia medicine Gastric mucosa Cancer research medicine.symptom Gastritis business Parietal cell |
| Zdroj: | The Journal of Pathology. 247:513-523 |
| ISSN: | 0022-3417 |
| DOI: | 10.1002/path.5214 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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