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

幽门螺杆菌（H.pylori）感染诱导从胃泌氧腺向萎缩和肠化生（IM）的“分化转换”，这是胃癌发展的一个危险因素。这种转换可能是由宿主对它的免疫反应引起的。但人们对这种“分化开关”的分子机制知之甚少。在本项目中，我们通过同源盒基因Cdx2和sry相关的HMG盒基因Sox2阐明了其中一个机制。Cdx2在胃细胞系、AGS和gcity中通过phospho-AKT/AKT / NF-κB信号通路受幽门螺杆菌刺激诱导，可发展为IM。另一方面，在胃细胞系中，当IFN-y、TNF-a、IL-1β和IL-4刺激时，th2相关细胞因子IL-4通过STAT6信号通路刺激后，AGS和MKN45中Sox2的表达水平均升高。而IFN-γ、IL-1β或TNF-a、thl相关细胞因子处理后，Sox2的表达变化不大。此外，幽门螺杆菌感染和IFN-γ刺激剂量依赖性地抑制il -4诱导的Sox2表达。siRNA转染抑制Sox2表达后，Cdx2的表达显著增加。因此，从“分化开关”的角度来看，幽门螺杆菌感染对Sox2的下调和thl优势宿主对Sox2的免疫应答可能促进胃萎缩和肠化生。

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'.