Salmonella typhimurium induces epithelial IL-8 expression via Ca2+-mediated activation of the NF-κB pathway
Salmonella typhimurium induces epithelial IL-8 expression via Ca2+-mediated activation of the NF-κB pathway
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DOI：
10.1172/jci8066
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发表时间：
2000-01-01
影响因子：
15.9
通讯作者：
Neish, AS
中科院分区：
文献类型：
--
作者：
Gewirtz, AT;Rao, AS;Neish, AS
肠道病原体鼠伤寒沙门氏菌与肠腔表面之间的相互作用会引发急性炎症反应，部分由上皮细胞分泌的趋化因子IL-8和其他促炎分子介导。本研究探讨了该病原体诱导生理极化模型肠上皮细胞分泌IL-8的机制。IL-8分泌由原型促炎细胞因子TNF-α和S.鼠伤寒沙门氏菌是NF-κ B依赖的。然而，S.鼠伤寒沙门氏菌，但不是由TNF-α，之前，并需要增加细胞内[Ca 2 +]。此外，通过受体依赖性（卡巴胆碱）或非依赖性（毒胡萝卜素，离子霉素）方式增加细胞内[Ca 2 +]的激动剂也诱导IL-8分泌。此外，S.鼠伤寒沙门氏菌突变体诱导I κ B-α降解、NF-κ B易位以及IL-8转录和分泌的能力与其诱导模型肠上皮细胞内[Ca 2 +]增加的能力精确相关，但与其侵袭这些细胞的能力无关。最后S。鼠伤寒沙门氏菌能诱导I κ B-α的钙依赖性磷酸化，而TNF-α则不能。由鼠伤寒沙门氏菌诱导的NF-κ B依赖性上皮炎性反应的激活通过Ca 2+介导的I κ B-α激酶的激活进行。这些观察结果提出了急性炎症反应的药物干预可以选择性地进行到特定类别的起始事件的可能性。
Interactions between the enteric pathogen Salmonella typhimurium and the luminal surface of the intestine provoke an acute inflammatory response, mediated in part by epithelial cell secretion of the chemokine IL-8 and other proinflammatory molecules. This study investigated the mechanism by which this pathogen induces IL-8 secretion in physiologically polarized model intestinal epithelia. IL-8 secretion induced by both the prototypical proinflammatory cytokine TNF-alpha and S. typhimurium was NF-kappa B dependent. However, NF-kappa B activation and IL-8 secretion induced by S. typhimurium, but not by TNF-alpha, was preceded by and required an increase in intracellular [Ca2+]. Additionally, agonists that increased intracellular [Ca2+] by receptor-dependent (carbachol) or independent (thapsigargin, ionomycin) means also induced IL-8 secretion. Furthermore, the ability of S. typhimurium mutants to induce I kappa B-alpha degradation, NF-kappa B translocation, and IL-8 transcription and secretion correlated precisely with their ability to induce an intracellular [Ca2+] increase in model intestinal epithelia, but not with their ability to invade these cells. Finally S. typhimurium, but not TNF-alpha, induced a Ca2+-dependent phosphorylation of I kappa B-alpha, These results indicate that S. typhimurium-induced activation of NF-kappa B-dependent epithelial inflammatory responses proceeds by a Ca2+-mediated activation of an I kappa B-alpha kinase. These observations raise the possibility that pharmacologic intervention of the acute inflammatory response can be selectively marched to the specific class of initiating event.