Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA.
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, Missouri, USA.
J Pathol. 2019 Apr;247(4):513-523. doi: 10.1002/path.5214. Epub 2019 Jan 24.
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.
胃黏膜的慢性炎症，常由自身免疫性胃炎和/或幽门螺杆菌感染引起，可导致胃酸分泌壁细胞萎缩，剩余细胞发生化生。组织学模式标志着从慢性胃炎向胃癌进展的关键步骤，但炎症诱导胃上皮细胞死亡的潜在机制尚不清楚。我们研究了与自身免疫和感染相关的 1 型细胞因子干扰素-γ（IFN-γ）对胃上皮细胞的直接作用。IFN-γ 应用于源自胃体腺（胃小体）的胃上皮细胞三维类器官培养物，这些细胞来自对照和 IFN-γ 受体缺陷型小鼠。胃小体还接受来自自身免疫介导性萎缩性胃炎（TxA23）小鼠模型中激活免疫细胞的上清液处理，这些上清液有或无 IFN-γ 表达。最后，在 TxA23 小鼠中进行了萎缩和化生严重程度的组织病理学分析，并与 TxA23×Ifng 小鼠进行了比较。胃小体培养物中的胃上皮细胞在基底外侧膜表达 IFN-γ 受体，并且当用 IFN-γ 以 IFN-γ 受体依赖性方式处理时，胃小体死亡。含有高水平 IFN-γ 的免疫细胞的上清液对胃小体具有高度毒性，当使用单克隆抗体中和 IFN-γ 或使用 Ifng 小鼠免疫细胞的上清液时，毒性减弱。最后，与 IFN-γ 充足的对照相比，TxA23×Ifng 小鼠几乎完全消除了癌前组织病理学萎缩和化生。我们确定 IFN-γ 是胃炎向胃萎缩和化生进展过程中壁细胞萎缩伴化生的关键促进剂。版权所有 © 2018 英国和爱尔兰病理学会。由 John Wiley & Sons，Ltd 出版。
