Lymphotoxin β receptor signalling executes Helicobacter pylori-driven gastric inflammation in a T4SS-dependent manner
Lymphotoxin β receptor signalling executes Helicobacter pylori-driven gastric inflammation in a T4SS-dependent manner
复制标题
DOI：
10.1136/gutjnl-2015-310783
复制
发表时间：
2017-08-01
期刊：
影响因子：
24.5
通讯作者：
Heikenwalder, Mathias
中科院分区：
文献类型：
--
作者：
Mejias-Luque, Raquel;Zoeller, Jessica;Heikenwalder, Mathias
目的光氧素β受体（LT β R）信号通路参与了不同组织中炎症相关肿瘤的发生发展。我们分析了LT β R和NF-κ B信号在幽门螺杆菌介导的胃炎症和病理中的作用。设计我们分析了幽门螺杆菌组织样本中NF-κ B信号通路的几种配体和受体、RelB、p52核转位和靶基因。通过原位杂交、免疫组化、Western blot和实时PCR分析，对幽门螺杆菌感染的不同程度的胃炎或早期胃肿瘤患者进行了研究。H激活LT β R的分子机制pylori进行体外评估，使用人胃癌细胞系和不同的H.幽门螺杆菌分离株。阻断或激动性激活LT β R对人类致病性H.结果实验组小鼠胃粘膜LT明显升高，NF-κ B B信号通路激活。幽门螺杆菌感染患者H. pylori以IV型分泌系统依赖但CagA非依赖的方式诱导LT β R-配体表达，导致替代NF-κ B途径的激活，在感染期间通过阻断经典NF-κ B进一步增强。在体内阻断LT β R信号传导抑制H。结论LT β R触发的胃上皮细胞NF-κ B B信号通路的激活激活可导致H. pylori诱导的慢性胃炎，是抑制H. pylori，而专门针对经典NF-κ B可能会通过增强替代途径而加剧病理。
Objective Lymphotoxin beta receptor (LT beta R) signalling has been implicated in inflammation-associated tumour development in different tissues. We have analysed the role of LT beta R and alternative NF-kappa B signalling in Helicobacter pylori-mediated gastric inflammation and pathology.Design We analysed several ligands and receptors of the alternative NF-kappa B pathway, RelB, p52 nuclear translocation and target genes in tissue samples of H. pylori-infected patients with different degrees of gastritis or early gastric tumours by in situ hybridisation, immunohistochemistry, Western blot and real-time PCR analyses. Molecular mechanisms involved in LT beta R activation by H. pylori were assessed in vitro using human gastric cancer cell lines and distinct H. pylori isolates. The effects of blocking or agonistically activating LT beta R on gastric pathology during challenge with a human pathogenic H. pylori strain were studied in a mouse model.Results Among the tested candidates, LT was significantly increased and activated alternative NF-kappa B signalling was observed in the gastric mucosa of H. pylori-infected patients. H. pylori induced LT beta R-ligand expression in a type IV secretion system-dependent but CagA-independent manner, resulting in activation of the alternative NF-kappa B pathway, which was further enhanced by blocking canonical NF-kappa B during infection. Blocking LT beta R signalling in vivo suppressed H. pylori-driven gastritis, whereas LT beta R activation in gastric epithelial cells of infected mice induced a broadened pro-inflammatory chemokine milieu, resulting in exacerbated pathology.Conclusions LT beta R-triggered activation of alternative NF-kappa B signalling in gastric epithelial cells executes H. pyloriinduced chronic gastritis, representing a novel target to restrict gastric inflammation and pathology elicited by H. pylori, while exclusively targeting canonical NF-kappa B may aggravate pathology by enhancing the alternative pathway.