Helicobacter pylori infection is the predominant risk factor for the development of gastric cancer. Risk is enhanced by specific H. pylori virulence factors, diet, and the inflammatory response. Chronic activation of T helper (Th) 1 and Th17 pathways contributes to prolonged inflammation; yet, higher expression of IL-17 receptor (IL-17RA) is a favorable prognostic marker for survival after gastric cancer diagnosis. The protective impact of IL-17RA signaling is not understood. To investigate if IL-17RA signaling protects during H. pylori-induced carcinogenesis, the transgenic InsGAStg/tg mouse, which is prone to H. pylori-induced gastric cancer, was utilized. InsGAStg/tg mice and InsGAStg/tgIl17ra-/- mice were infected with a cag type 4 secretion system (T4SS) positive H. pylori strain for up to 6 months. Six weeks post-infection, IL-17RA deficiency led to increased bacterial burden, increased gastritis, and development of lymphoid follicles. Increased inflammation was associated with heightened cellular proliferation and earlier loss of parietal and chief cells in InsGAStg/tgIl17ra-/- mice. Gastric cancers developed more frequently by 3- and 6-months post-infection in H. pylori-infected InsGAStg/tgIl17ra-/- mice compared to InsGAStg/tg mice. Chronic inflammation was exacerbated with IL-17RA deficiency, characterized by elevated Th1/Th17 cytokines, increased B cell infiltration, and enhanced IgA production, despite reduced expression of the polymeric immunoglobulin receptor. Further, paragastric lymph nodes of InsGAStg/tgIl17ra-/- mice were enlarged relative to controls and displayed altered gene expression profiles. Increased inflammation was accompanied by a significant increase in Cybb expression, which encodes NADPH oxidase 2, suggesting that increased oxidative damage may occur in the absence of IL-17RA. Further, there is increased phosphorylation of histone 2AX in IL-17RA deficient mice, indicating that the DNA damage response is highly activated. These data suggest that IL-17RA signaling activates a protective pathway to prevent excessive inflammation which otherwise can lead to increased oxidative stress, DNA damage, and drive gastric carcinogenesis after H. pylori infection.

中文翻译：

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IL-17 信号传导可预防幽门螺杆菌诱导的胃癌。


幽门螺杆菌感染是胃癌发展的主要危险因素。特定的幽门螺杆菌毒力因子、饮食和炎症反应会增加风险。辅助性 T 细胞 （Th） 1 和 Th17 通路的慢性激活导致长期炎症;然而，IL-17 受体 （IL-17RA） 的较高表达是胃癌诊断后生存的有利预后标志物。IL-17RA 信号转导的保护作用尚不清楚。为了研究 IL-17RA 信号转导是否在幽门螺杆菌诱导的致癌过程中起保护作用，使用了易患幽门螺杆菌诱导的胃癌的转基因 InsGAStg/tg 小鼠。InsGAStg/tg 小鼠和 InsGAStg/tgIl17ra-/- 小鼠感染 cag 4 型分泌系统 （T4SS） 阳性幽门螺杆菌菌株长达 6 个月。感染后 6 周，IL-17RA 缺乏导致细菌负荷增加、胃炎增加和淋巴滤泡发育。炎症增加与 InsGAStg/tgIl17ra-/- 小鼠细胞增殖增加和壁细胞和主细胞的早期丢失有关。与 InsGAStg/tg 小鼠相比，幽门螺杆菌感染的 InsGAStg/tgIl17ra-/- 小鼠在感染后 3 个月和 6 个月更频繁地发生胃癌。IL-17RA 缺乏症加剧了慢性炎症，其特征是 Th1/Th17 细胞因子升高、B 细胞浸润增加和 IgA 产生增加，尽管聚合物免疫球蛋白受体的表达降低。此外，InsGAStg/tgIl17ra-/- 小鼠的胃旁淋巴结相对于对照组增大，并显示改变的基因表达谱。 炎症增加伴随着编码 NADPH 氧化酶 2 的 Cybb 表达的显着增加，表明在没有 IL-17RA 的情况下可能会发生氧化损伤增加。此外，IL-17RA 缺陷小鼠组蛋白 2AX 的磷酸化增加，表明 DNA 损伤反应高度激活。这些数据表明，IL-17RA 信号转导激活保护性通路以防止过度炎症，否则会导致氧化应激增加、DNA 损伤，并驱动幽门螺杆菌感染后的胃癌发生。