Analysis of differentiation system in the stomach by the immune response to Helicobactor pylori infection

通过对幽门螺杆菌感染的免疫反应分析胃中的分化系统

• 批准号: 17590608
• 负责人: IMATANI Akira
• 金额: $ 2.3万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590608/
• 关键词: differentiation; regulation of expression; signaling; immunology; stomach

Helicobacter pylori (H.pylori) infection induces the 'switch of differentiation' from gastric oxytinc glands to atrophy and intestinal metaplasia(IM), which are a risk factor in gastric cancer development. This switch may be induced by host immune response to it. But little is known about the molecular mechanism of this 'switch of differentiation'. In this project, we have clarified one of the mechanisms through a homeobox gene Cdx2 and SRY-related HMG box gene Sox2. Cdx2, which can be developed IM, was induced by the H.pylori stimulation through phospho-AKT/AKT / NF-κB signaling pathway in gastric cell lines, AGS and GCIY. On the other hand, when stimulating with IFN-y, TNF-a, IL-1β and IL-4 in gastric cell lines, the expression level of Sox2 increased in both AGS and MKN45 after the stimulation with IL-4, a Th2-related cytokine, through STAT6 signaling. But little changes of Sox2 expression were observed after the treatment with IFN-γ, IL-1β, or TNF-a, Thl-related cytokine. Moreover, H. pylori infection and IFN-γ stimulation dose-dependently inhibited IL-4-induced expression of Sox2. The inhibition of Sox2 expression by siRNA transfection substantially increased the expression of Cdx2. Therefore, the down-regulation of Sox2 by H.pylori infection and Thl-dominant host immune response to it may promote gastric atrophy and intestinal metaplasia in the view of 'switch of differentiation'.

幽门螺杆菌（Helicobacter pylori，H.pylori）感染诱导胃泌酸腺向萎缩和肠上皮化生（intestinal metaplasia，IM）的“分化转换”，这是胃癌发展的危险因素。这种“分化开关”可能是由宿主对它的免疫反应所诱导的，但目前对这种“分化开关”的分子机制知之甚少。在本项目中，我们通过同源异型盒基因Cdx 2和SRY相关的HMG盒基因Sox 2阐明了其中一个机制。幽门螺杆菌（H.pylori）通过磷酸化AKT/AKT / NF-κB信号通路诱导胃上皮细胞株AGS和GCIY表达Cdx 2，Cdx 2可在胃上皮细胞株GCIY和AGS中发生IM。另一方面，当在胃细胞系中用IFN-γ、TNF-α、IL-1β和IL-4刺激时，在用IL-4（一种Th 2相关细胞因子）刺激后，Sox 2的表达水平在AGS和MKN 45中均通过STAT 6信号传导而增加。IFN-γ、IL-1β、TNF-α、Th 1相关细胞因子对Sox 2表达无明显影响。此外，H. pylori感染和IFN-γ刺激剂量依赖性地抑制IL-4诱导的Sox 2表达。通过siRNA转染抑制Sox 2表达显著增加Cdx 2的表达。因此，从“分化转换”的角度来看，H.pylori感染引起的Sox 2表达下调以及Thl优势的宿主免疫应答可能促进了胃萎缩和肠上皮化生的发生。