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I nteractions 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.