IFN-γ inhibits gastric carcinogenesis by inducing epithelial cell autophagy and T-cell apoptosis.
IFN-γ inhibits gastric carcinogenesis by inducing epithelial cell autophagy and T-cell apoptosis.
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DOI：
10.1158/0008-5472.can-10-4009
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发表时间：
2011-06-15
期刊：
影响因子：
11.2
通讯作者：
Wang TC
中科院分区：
文献类型：
--
作者：
Tu SP;Quante M;Bhagat G;Takaishi S;Cui G;Yang XD;Muthuplani S;Shibata W;Fox JG;Pritchard DM;Wang TC
干扰素γ (IFN-γ)介导对细菌感染和自身免疫性疾病的反应，但它也是一种重要的肿瘤抑制因子。慢性幽门螺杆菌感染后胃黏膜中IFN-γ上调；然而，它在炎症相关的胃癌发生中是否起着积极或消极的作用尚不清楚。为了研究这个问题，我们培育了一只H+/K+-ATPase-IFN-γ转基因小鼠，它在胃粘膜中过表达小鼠IFN-γ。与预期的促炎作用相反，我们发现IFN-γ过表达不能诱导胃炎，而是抑制IL-1β (IL-1β)和/或幽门螺杆菌感染诱导的胃癌发生。IFN-γ通过Fas诱导CD4 T细胞凋亡抑制Th1和Th17免疫应答。IFN-γ也通过增加Beclin-1的表达诱导胃上皮细胞自噬。最后，在胃上皮中，IFN-γ也抑制IL-1β-和幽门螺杆菌诱导的上皮细胞凋亡、增殖和Dckl1+细胞扩增。综上所述，我们的研究结果表明，IFN-γ通过诱导自噬程序抑制假定的胃祖细胞增殖和减少上皮细胞凋亡，从而协同抑制胃粘膜的细菌感染和癌变。
Interferon-gamma (IFN-γ) mediates responses to bacterial infection and autoimmune disease but it is also an important tumor suppressor. IFN-γ 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 pro-inflammatory role during infection, we found that IFN-γ overexpression failed to induce gastritis and instead inhibited gastric carcinogenesis induced by IL-1beta (IL-1β) and/or Helicobacter infection. Th1 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. Lastly, 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.