Salmonella typhimurium induces epithelial IL-8 expression via Ca2+-mediated activation of the NF-kappa B pathway

Interactions between the enteric pathogen Salmonella typhimurium and the lu minal surface of the intestine provoke an acute inflammatory response, medi ated in part by epithelial cell secretion of the chemokine IL-8 and other p roinflammatory molecules. This study investigated the mechanism by which th is pathogen induces IL-8 secretion in physiologically polarized model intes tinal epithelia. IL-8 secretion induced by both the prototypical proinflamm atory cytokine TNF-alpha and S. typhimurium was NF-kappa B dependent. Howev er, 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 intracellula r [Ca2+]. Additionally, agonists that increased intracellular [Ca2+] by rec eptor-dependent (carbachol) or independent (thapsigargin, ionomycin) means also induced IL-8 secretion. Furthermore, the ability of S. typhimurium mut ants to induce I kappa B-alpha degradation, NF-kappa B translocation, and I L-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 n ot 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 ac tivation of an I kappa B-alpha kinase. These observations raise the possibi lity that pharmacologic intervention of the acute inflammatory response can be selectively marched to the specific class of initiating event.