Salmonella infection upregulates the leaky protein claudin-2 in intestinal epithelial cells.
Salmonella infection upregulates the leaky protein claudin-2 in intestinal epithelial cells.
复制标题
DOI：
10.1371/journal.pone.0058606
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Sun J
中科院分区：
文献类型：
--
作者：
Zhang YG;Wu S;Xia Y;Sun J
紧密连接密封相邻上皮细胞之间的空间。越来越多的证据表明，紧密连接蛋白在人类疾病的发病机制中起着关键作用。紧密连接蛋白是紧密连接蛋白家族的一员，在人类中有24个成员。为了调节细胞功能，紧密连接蛋白通过其胞质结构域与膜和支架蛋白在结构和功能上相互作用。特别是，已知claudin-2是一种导致炎症性肠病和结肠癌的渗漏蛋白。然而，claudin-2在肠道细菌感染中的参与仍然未知。我们假设沙门氏菌为了自身的利益提高了泄漏蛋白claudin-2，以促进结肠中的细菌入侵。使用沙门氏菌-结肠炎小鼠模型和培养的结肠上皮细胞，我们发现致病性沙门氏菌定植显著增加了肠中claudin-2蛋白和mRNA的水平，但不是结肠中claudin-3或claudin-7的水平，以时间依赖性的方式。免疫组化结果显示，claudin-2在感染后沿着腺窝-绒毛轴表达。在体外，沙门氏菌刺激人肠上皮细胞系SKCO 15和HT 29 C19 A中的claudin-2表达。通过siRNA敲低的进一步分析揭示了密蛋白-2与沙门氏菌诱导的细胞通透性升高相关。具有紧密连接蛋白-2敲低的上皮细胞比具有正常紧密连接蛋白-2表达的对照细胞具有显著更少的内化沙门氏菌。抑制剂分析表明，这种调节是通过激活EGFR途径和下游蛋白JNK介导的。我们已经证明沙门氏菌靶向紧密连接蛋白claudin-2以促进细菌入侵。我们推测，这种屏障功能的破坏有助于细菌与宿主细胞相互作用的新机制，并表明阻断claudin-2作为预防细菌入侵的潜在治疗策略的可能性。
Tight junctions seal the space between adjacent epithelial cells. Mounting evidence suggests that tight junction proteins play a key role in the pathogenesis of human disease. Claudin is a member of the tight junction protein family, which has 24 members in humans. To regulate cellular function, claudins interact structurally and functionally with membrane and scaffolding proteins via their cytoplasmic domain. In particular, claudin-2 is known to be a leaky protein that contributes to inflammatory bowel disease and colon cancer. However, the involvement of claudin-2 in bacterial infection in the intestine remains unknown. We hypothesized that Salmonella elevates the leaky protein claudin-2 for its own benefit to facilitate bacterial invasion in the colon. Using a Salmonella-colitis mouse model and cultured colonic epithelial cells, we found that pathogenic Salmonella colonization significantly increases the levels of claudin-2 protein and mRNA in the intestine, but not that of claudin-3 or claudin-7 in the colon, in a time-dependent manner. Immunostaining studies showed that the claudin-2 expression along the crypt-villous axis postinfection. In vitro, Salmonella stimulated claudin-2 expression in the human intestinal epithelial cell lines SKCO15 and HT29C19A. Further analysis by siRNA knockdown revealed that claudin-2 is associated with the Salmonella-induced elevation of cell permeability. Epithelial cells with claudin-2 knockdown had significantly less internalized Salmonella than control cells with normal claudin-2 expression. Inhibitor assays demonstrated that this regulation is mediated through activation of the EGFR pathway and the downstream protein JNK. We have shown that Salmonella targets the tight junction protein claudin-2 to facilitate bacterial invasion. We speculate that this disruption of barrier function contributes to a new mechanism by which bacteria interact with their host cells and suggests the possibility of blocking claudin-2 as a potential therapeutic strategy to prevent bacterial invasion.
登录
查看更多内容
影响因子：
5.2
作者：
Van Itallie CM;Holmes J;Bridges A;Anderson JM
通讯作者：
Anderson JM
DOI：
10.1152/ajpgi.90227.2008
发表时间：
2008-11-01
影响因子：
4.5
作者：
Ewaschuk, Julia B.;Diaz, Hugo;Madsen, Karen L.
通讯作者：
Madsen, Karen L.
影响因子：
168.9
作者：
WYATT, J;VOGELSANG, H;LOCHS, H
通讯作者：
LOCHS, H
影响因子：
24.5
作者：
HOLLANDER, D
通讯作者：
HOLLANDER, D
Claudin-1和Claudin-2表达在炎症性肠病中升高，可能有助于早期的肿瘤转化。
影响因子：
5
作者：
Weber, Christopher R.;Nalle, Sam C.;Tretiakova, Maria;Rubin, David T.;Turner, Jerrold R.
通讯作者：
Turner, Jerrold R.