title: Salmonella typhimurium induces epithelial IL-8 expression via Ca(2+)-mediated activation of the NF-kappaB pathway.
abstract: 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-kappaB dependent. However, NF-kappaB activation and IL-8 secretion induced by S. typhimurium, but not by TNF-alpha, was preceded by and required an increase in intracellular [Ca(2+)]. Additionally, agonists that increased intracellular [Ca(2+)] by receptor-dependent (carbachol) or independent (thapsigargin, ionomycin) means also induced IL-8 secretion. Furthermore, the ability of S. typhimurium mutants to induce IkappaB-alpha degradation, NF-kappaB translocation, and IL-8 transcription and secretion correlated precisely with their ability to induce an intracellular [Ca(2+)] increase in model intestinal epithelia, but not with their ability to invade these cells. Finally, S. typhimurium, but not TNF-alpha, induced a Ca(2+)-dependent phosphorylation of IkappaB-alpha. These results indicate that S. typhimurium-induced activation of NF-kappaB-dependent epithelial inflammatory responses proceeds by a Ca(2+)-mediated activation of an IkappaB-alpha 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.
authors.affiliation: Epithelial Pathobiology Unit, Department of Pathology Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: A T
authors.initials: AT
authors.lastname: Gewirtz
authors.forename: A S
authors.initials: AS
authors.lastname: Rao
authors.forename: P O
authors.initials: PO
authors.lastname: Simon
authors.forename: D
authors.initials: D
authors.lastname: Merlin
authors.forename: D
authors.initials: D
authors.lastname: Carnes
authors.forename: J L
authors.initials: JL
authors.lastname: Madara
authors.forename: A S
authors.initials: AS
authors.lastname: Neish
mesh_terms: D002118:Calcium / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology; D006801:Humans; D020672:I-kappa B Proteins; D007375:Interleukin-1 / Q000494:pharmacology; D016209:Interleukin-8 / Q000096:biosynthesis*; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000382:microbiology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000502:physiology*; D010766:Phosphorylation; D012486:Salmonella typhimurium / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D007375:Interleukin-1; D016209:Interleukin-8; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D002118:Calcium