Helicobacter pylori virulence factors affecting gastric proton pump expression and acid secretion
Helicobacter pylori virulence factors affecting gastric proton pump expression and acid secretion
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DOI：
10.1152/ajpgi.00099.2015
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发表时间：
2015-08-01
影响因子：
4.5
通讯作者：
Smolka, Adam J.
中科院分区：
文献类型：
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作者：
Hammond, Charles E.;Beeson, Craig;Smolka, Adam J.
急性幽门螺杆菌感染胃上皮细胞和人胃活检可抑制H， k - atp酶α亚基（HK α）基因表达，抑制酸分泌，引起短暂的低氯酸，支持胃幽门螺杆菌定植。缺乏cag致病性岛（cag PAI）基因cagL、cagE或cagM的幽门螺杆菌菌株感染后，不会将CagA转移到宿主细胞中，也不会诱导白细胞介素-8的分泌，因此不会抑制HK α的表达，缺乏cag致病性岛（cag PAI）基因的菌株也不会诱导IL-8。为了验证介导CagA易位或IL-8诱导的毒力因子以外的毒力因子通过激活NF-kappa B参与HK α抑制的假设，将含有完整或突变的NF-kappa B结合位点的HK α启动子- luc报告基因构建体转染了野生型幽门螺杆菌菌株7.13，这些菌株缺乏负责CagA易位和/或IL-8诱导的cag PAI基因（CagA, cag zeta, cag epsilon， cagZ和cag beta）。或者缺乏编码两种肽聚糖水解酶（slt和cag γ）的基因。分别采用荧光法、免疫印迹法和ELISA法检测幽门螺杆菌诱导的AGS细胞HK α启动子活性、易位CagA和IL-8分泌。采用显微生理法测定人胃活检组织的胃酸分泌。综上所述，数据表明HK α抑制不依赖于IL-8的表达，CagA易位与slt和cag γ编码的幽门螺杆菌转糖基酶共同参与NF-kappa b依赖性HK α抑制和酸抑制。这一发现意义重大，因为除了CagA和IL-8分泌外，幽门螺杆菌因子现在与短暂性低氯酸血症有关，低氯酸血症促进胃定植，并可能引发上皮进展为肿瘤。
Acute Helicobacter pylori infection of gastric epithelial cells and human gastric biopsies represses H, K-ATPase alpha subunit (HK alpha) gene expression and inhibits acid secretion, causing transient hypochlorhydria and supporting gastric H. pylori colonization. Infection by H. pylori strains deficient in the cag pathogenicity island (cag PAI) genes cagL, cagE, or cagM, which do not transfer CagA into host cells or induce interleukin-8 secretion, does not inhibit HK alpha expression, nor does a cagA-deficient strain that induces IL-8. To test the hypothesis that virulence factors other than those mediating CagA translocation or IL-8 induction participate in HK alpha repression by activating NF-kappa B, AGS cells transfected with HK alpha promoter-Luc reporter constructs containing an intact or mutated NF-kappa B binding site were infected with wild-type H. pylori strain 7.13, isogenic mutants lacking cag PAI genes responsible for CagA translocation and/or IL-8 induction (cagA, cag zeta, cag epsilon, cagZ, and cag beta), or deficient in genes encoding two peptidoglycan hydrolases (slt and cag gamma). H. pylori-induced AGS cell HK alpha promoter activities, translocated CagA, and IL-8 secretion were measured by luminometry, immunoblotting, and ELISA, respectively. Human gastric biopsy acid secretion was measured by microphysiometry. Taken together, the data showed that HK alpha repression is independent of IL-8 expression, and that CagA translocation together with H. pylori transglycosylases encoded by slt and cag gamma participate in NF-kappa B-dependent HK alpha repression and acid inhibition. The findings are significant because H. pylori factors other than CagA and IL-8 secretion are now implicated in transient hypochlorhydria which facilitates gastric colonization and potential triggering of epithelial progression to neoplasia.