Department of Medicine, Medicine/Gastro CSB 921E, Medical University of South Carolina, Charleston, SC 29425, USA.
J Gastroenterol. 2012 Jun;47(6):609-18. doi: 10.1007/s00535-012-0592-1. Epub 2012 May 8.
Infection of the human stomach mucosa by Helicobacter pylori induces strong inflammatory responses and a transitory hypochlorhydria which can progress in ~2 % of patients to atrophic gastritis, dysplasia, or gastric adenocarcinoma. H. pylori infection of gastric biopsies or cultured gastric epithelial cells in vitro represses the activity of endogenous or transfected promoter of the alpha-subunit (HKα) of gastric H,K-adenosine triphosphatase (H,K-ATPase), the parietal cell enzyme mediating acid secretion. Some mechanistic details of H. pylori-mediated repression of HKα and ensuing hypochlorhydria have been recently elucidated. H. pylori strains expressing a type IV secretion system (T4SS) encoded by the cag pathogenicity island are known to upregulate the transcription factor nuclear factor (NF)-κB. The NF-κB-binding regions in the HKα promoter were identified and shown to repress its transcriptional activity. Interaction studies have indicated that although active phosphorylated NF-κB p65 is present in infected cells, an NF-κB p50/p65 heterodimeric complex fails to bind to the HKα promoter. Point mutations at -159 and -161 bp in the HKα promoter NF-κB binding sequence prevent the binding of NF-κB p50 and prevent H. pylori repression of point-mutated HKα promoter activity. The T4SS factors CagL, CagE, CagM, and possibly CagA and the lytic transglycosylase Slt, are mechanistically involved in NF-κB activation and repression of HKα transcription. CagL, a T4SS pilus component, binds to the integrin α(5)β(1) to mediate translocation of virulence factors into the host cell and initiate signaling. During acute H. pylori infection, CagL dissociates ADAM 17 (a disintegrin and a metalloprotease 17) from the integrin α(5)β(1) complex and stimulates ADAM17-dependent release of heparin-binding epidermal growth factor (HB-EGF), EGF receptor (EGFR) stimulation, ERK1/2 kinase activation, and NF-κB-mediated repression of HKα. These studies suggest that H. pylori inhibits HKα gene expression by an integrin α(5)β(1) → ADAM17 → HB-EGF → EGFR → ERK1/2 → NF-κB pathway mediating NF-κB p50 homodimer binding to the HKα promoter. Here we review the molecular basis and recent progress of this novel pathogen-dependent mechanism of H,K-ATPase inhibition, which contributes significantly to our current understanding of H. pylori pathophysiology.
人类胃黏膜感染幽门螺杆菌会引起强烈的炎症反应和短暂的低胃酸分泌，这种情况在约 2%的患者中会进展为萎缩性胃炎、发育不良或胃腺癌。幽门螺杆菌感染胃活检或体外培养的胃上皮细胞会抑制胃 H+，K+-三磷酸腺苷酶（H + ，K-ATPase）的α亚基（HKα）内源性或转染启动子的活性，该酶是介导胃酸分泌的壁细胞酶。最近已经阐明了幽门螺杆菌介导的 HKα抑制和随之而来的低胃酸分泌的一些机制细节。已知表达 cag 致病岛编码的 IV 型分泌系统（T4SS）的幽门螺杆菌菌株会上调转录因子核因子（NF）-κB。已鉴定出 HKα启动子中的 NF-κB 结合区，并表明其可抑制其转录活性。相互作用研究表明，尽管感染细胞中存在活性磷酸化的 NF-κB p65，但 NF-κB p50/p65 异二聚体复合物不能与 HKα 启动子结合。HKα 启动子 NF-κB 结合序列中的-159 和-161 位点突变可阻止 NF-κB p50 结合并阻止幽门螺杆菌抑制点突变 HKα 启动子活性。T4SS 因子 CagL、CagE、CagM，以及可能的 CagA 和溶菌转糖苷酶 Slt，在 NF-κB 激活和 HKα 转录抑制中具有机制作用。T4SS 钉毛成分 CagL 与整合素 α（5）β（1）结合，介导毒力因子向宿主细胞的易位并启动信号转导。在急性幽门螺杆菌感染期间，CagL 从整合素 α（5）β（1）复合物中解离 ADAM17（一种去整合素和金属蛋白酶 17），并刺激 ADAM17 依赖性肝素结合表皮生长因子（HB-EGF）释放、EGF 受体（EGFR）刺激、ERK1/2 激酶激活和 NF-κB 介导的 HKα 抑制。这些研究表明，幽门螺杆菌通过整合素 α（5）β（1）→ADAM17→HB-EGF→EGFR→ERK1/2→NF-κB 途径抑制 HKα 基因表达，该途径介导 NF-κB p50 同源二聚体与 HKα 启动子结合。在这里，我们综述了这种新型依赖病原体的 H + ，K+-ATPase 抑制机制的分子基础和最新进展，这对我们当前对幽门螺杆菌病理生理学的理解有重要贡献。
