Department of Medicine, Gastroenterology & Hepatology Division, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Department of Biostatistics and Computational Biology, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, USA.
J Inflamm (Lond). 2010 Aug 12;7:42. doi: 10.1186/1476-9255-7-42.
Tumor necrosis factor alpha (TNF-alpha)is a host inflammatory factor. Bacteria increase TNF-alpha expression in a variety of human diseases including infectious diseases, inflammatory bowel diseases, and cancer. It is unknown, however, how TNF-alpha directly modulates bacterial protein expression during intestinal infection and chronic inflammation. In the current study, we hypothesize that Salmonella typhimurium senses TNF-alpha and show that TNF-alpha treatment modulates Salmonella virulent proteins (called effectors), thus changing the host-bacterial interaction in intestinal epithelial cells. We investigated the expression of 23 Salmonella effectors after TNF-alpha exposure. We found that TNF-alpha treatment led to differential effector expression: effector SipA was increased by TNF-alpha treatment, whereas the expression levels of other effectors, including gogB and spvB, decreased in the presence of TNF-alpha. We verified the protein expression of Salmonella effectors AvrA and SipA by Western blots. Furthermore, we used intestinal epithelial cells as our experimental model to explore the response of human intestinal cells to TNF-alpha pretreated Salmonella. More bacterial invasion was found in host cells colonized with Salmonella strains pretreated with TNF-alpha compared to Salmonella without TNF-alpha treatment. TNF-alpha pretreated Salmonella induced higher proinflammatory JNK signalling responses compared to the Salmonella strains without TNF-alpha exposure. Exposure to TNF-alpha made Salmonella to induce more inflammatory cytokine IL-8 in intestinal epithelial cells. JNK inhibitor treatment was able to suppress the effects of TNF-pretreated-Salmonella in enhancing expressions of phosphorylated-JNK and c-jun and secretion of IL-8. Overall, our study provides new insights into Salmonella-host interactions in intestinal inflammation.
肿瘤坏死因子-α（TNF-α）是一种宿主炎症因子。在包括传染病、炎症性肠病和癌症在内的多种人类疾病中，细菌会增加 TNF-α的表达。然而，目前尚不清楚 TNF-α如何在肠道感染和慢性炎症期间直接调节细菌的蛋白质表达。在本研究中，我们假设沙门氏菌能感知 TNF-α，并表明 TNF-α 处理可调节沙门氏菌毒力蛋白（称为效应蛋白），从而改变肠道上皮细胞中的宿主-细菌相互作用。我们研究了 TNF-α 暴露后 23 种沙门氏菌效应蛋白的表达情况。结果发现，TNF-α 处理可导致效应蛋白的差异表达：SipA 的表达水平增加，而其他效应蛋白（包括 gogB 和 spvB）的表达水平在 TNF-α存在的情况下降低。我们通过 Western blot 验证了沙门氏菌效应蛋白 AvrA 和 SipA 的蛋白表达。此外，我们使用肠上皮细胞作为实验模型，以探索人类肠道细胞对 TNF-α预处理的沙门氏菌的反应。与未用 TNF-α 处理的沙门氏菌相比，用 TNF-α 预处理的沙门氏菌感染的宿主细胞中发现有更多的细菌入侵。与未用 TNF-α 暴露的沙门氏菌相比，TNF-α 预处理的沙门氏菌可诱导更高的促炎 JNK 信号反应。TNF-α 暴露使沙门氏菌在肠上皮细胞中诱导更多的炎症细胞因子 IL-8 的表达。JNK 抑制剂处理能够抑制 TNF-预处理的沙门氏菌增强磷酸化-JNK 和 c-jun 的表达和 IL-8 分泌的作用。总的来说，本研究为肠道炎症中沙门氏菌与宿主的相互作用提供了新的见解。
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