RIP3介导肠化胃上皮细胞IL-33的表达

RIP3 mediates IL-33 production in gastric epithelial cells with intestinal metaplasia

目的探索受体相互作用蛋白激酶3(receptor-interacting protein kinase 3,RIP3)信号通路与胃黏膜肠上皮化生(gastric intestinal metaplasia,GIM)的关系,及其对炎性细胞因子的调控作用.方法收集健康对照,患有慢性非萎缩性胃炎、GIM和异型增生的胃黏膜组织标本,通过免疫组化和qRTPCR分析RIP3在GIM中的表达情况.用脱氧胆酸钠(sodium desoxycholate,DCA)刺激GES-1人胃黏膜上皮细胞系,western blot观察肠上皮化生的关键基因CDX2与RIP3信号通路的关系,及RIP3信号通路对炎性细胞因子的调控.结果与对照组和慢性非萎缩性胃炎组相比,GIM组和异型增生组的胃黏膜RIP3 mRNA表达上调;同时GIM组和异型增生组胃上皮细胞RIP3蛋白水平表达上调.受DCA刺激的GES-1细胞,RIP3信号通路相关蛋白表达与CDX2蛋白表达均上调,伴随着IL-33表达的上调;RIP3信号通路的特异性抑制剂(necrostatin-1,Nec-1)对CDX2表达无影响,但可显著下调RIP3信号通路相关蛋白及IL-33的表达.结论 RIP3信号通路对GIM的发生无影响,然而其可能通过调控肠化的胃上皮细胞IL-33的表达影响GIM进展,提示其可能成为阻止GIM进展的潜在治疗靶点.

AIM To explore the relationship between receptor- interacting protein kinase 3 （RIP3） signaling pathway and gastric intestinal metaplasia （GIM）, and the regulatory effect of this signaling pathway on inflammatory cytokines. METHODS Gastric tissues from healthy controls, patients with chronic non-atrophic gastritis, patients with GIM, and patients with dysplasia were collected to detect the expression of RIP3 in GIM by immunohistochemistry and RT-PCR. Human gastric epithelial cell line GES-1 was stimulated with sodium deoxycholate （DCA） to observe the relationship between CDX2, a key gene involved in intestinal metaplasia, and RIP3 signaling pathway. The regulation of inflammatory cytokines by RIP3 was also assessed. RESULTS Compared with the control and chronic non-atrophic gastritis groups, the expression of RIP3 mRNA in the gastric mucosa of GIM patients and dysplasia patients was up-regulated, and the expression of RIP3 protein in the gastric epithelium of GIM patients and dysplasia patients was also up-regulated. In GES-1 cells stimulated with DCA, the expression of CDX2 protein and the RIP3 signaling pathway-associated proteins was increased in a concentration-dependent manner, accompanied by up-regulation of IL-33 expression. Necrostatin-1 （Nec-1）, a specific inhibitor of the RIP3 signaling pathway, had no effect on CDX2 expression, but significantly down-regulated the expression of RIP3 and IL-33.CONCLUSION RIP3 has no effect on the occurrence of GIM, but it may affect GIM progression by regulating the expression of IL-33 in gastric epithelial cells with intestinal metaplasia, suggesting that it may be a potential therapeutic target for preventing GIM progression.