Helicobacter pylori dupA Is Polymorphic, and Its Active Form Induces Proinflammatory Cytokine Secretion by Mononuclear Cells
Helicobacter pylori dupA Is Polymorphic, and Its Active Form Induces Proinflammatory Cytokine Secretion by Mononuclear Cells
复制标题
DOI：
10.1086/653587
复制
发表时间：
2010-07-15
影响因子：
6.4
通讯作者：
Atherton, John C.
中科院分区：
文献类型：
--
作者：
Hussein, Nawfal R.;Argent, Richard H.;Atherton, John C.
背景。幽门螺杆菌感染具有新描述的毒力因子——十二指肠溃疡促进基因 A (dupA)——与十二指肠溃疡和胃炎症增加有关。方法。对 34 个菌株的 dupA 位点进行了测序。产生一组 dupA 突变体并与人胃上皮细胞和外周血单核细胞共培养；测量促炎细胞因子的释放。在人胃活检标本中测量 IL8 表达，并与感染菌株的 dupA 和 cagA 状态相关。结果。大多数幽门螺杆菌菌株的 dupA 等位基因比之前描述的 dupA 等位基因更长（1884 bp；dupA1），尽管有些菌株有截短的版本（dupA2）。与最典型的幽门螺杆菌毒力决定因素 cag 致病岛 (cag PaI) 不同，dupA 类型均不会诱导胃上皮细胞释放白细胞介素 (IL)-8。然而，与 dupA 阴性菌株引起的感染相比，dupA 阳性菌株引起的感染与人胃中更高水平的粘膜 IL-8 信使 RNA 表达相关。为了解释这一悖论，我们发现 dupA1（但不是 dupA2 或 cag PaI）显着增加了幽门螺杆菌诱导的 CD14+ 单核细胞产生 IL-12p40 和 IL-12p70。其他 T 辅助细胞 1 相关细胞因子也被适度诱导。结论。我们认为，有毒力的幽门螺杆菌菌株通过 cag 编码蛋白刺激上皮细胞，并通过 dupA1 产品刺激单核炎症细胞，从而引起炎症。
Background. Infection with Helicobacter pylori possessing a newly described virulence factor-duodenal ulcer-promoting gene A (dupA)-has been associated with duodenal ulceration and increased gastric inflammation.Methods. The dupA locus of 34 strains was sequenced. A panel of dupA mutants was generated and cocultured with human gastric epithelial cells and peripheral blood mononuclear cells; proinflammatory cytokine release was measured. IL8 expression was measured in human gastric biopsy specimens and related to the dupA and cagA status of infecting strains.Results. Most H. pylori strains had a dupA allele that was longer (1884 bp; dupA1) than previously described dupA alleles, although some had truncated versions (dupA2). Unlike the best-characterized H. pylori virulence determinant, the cag pathogenicity island (cag PaI), neither dupA type induced release of interleukin (IL)-8 from gastric epithelial cells. However, infections due to dupA-positive strains were associated with higher-level mucosal IL-8 messenger RNA expression in the human stomach than were infections due to dupA-negative strains. To explain this paradox, we found that dupA1 (but not dupA2 or the cag PaI) substantially increased H. pylori-induced IL-12p40 and IL-12p70 production from CD14(+) mononuclear cells. Other T helper 1-associated cytokines were also modestly induced.Conclusion. We suggest that virulent H. pylori strains cause inflammation by stimulating epithelial cells through cag-encoded proteins and mononuclear inflammatory cells through dupA1 products.