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-α and S. typhimurium was NF-κB dependent. However, NF-κB activation and IL-8 secretion induced by S. typhimurium, but not by TNF-α, 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 IκB-α degradation, NF-κB 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-α, induced a Ca2+-dependent phosphorylation of IκB-α. These results indicate that S. typhimurium–induced activation of NF-κB–dependent epithelial inflammatory responses proceeds by a Ca2+-mediated activation of an IκB-α kinase. These observations raise the possibility that pharmacologic intervention of the acute inflammatory response can be selectively matched to the specific class of initiating event.
Andrew T. Gewirtz, Anjali S. Rao, Peter O. Simon Jr., Didier Merlin, Denice Carnes, James L. Madara, Andrew S. Neish
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