Salmonella typhimurium induces epithelial IL-8 expression via Ca(2+)-mediated activation of the NF-kappaB pathway

J Clin Invest. 2000 Jan;105(1):79-92. doi: 10.1172/JCI8066.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Calcium / physiology*
  • DNA-Binding Proteins / physiology
  • Humans
  • I-kappa B Proteins*
  • Interleukin-1 / pharmacology
  • Interleukin-8 / biosynthesis*
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / microbiology*
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / physiology*
  • Phosphorylation
  • Salmonella typhimurium / physiology*
  • Tumor Necrosis Factor-alpha / pharmacology


  • DNA-Binding Proteins
  • I-kappa B Proteins
  • Interleukin-1
  • Interleukin-8
  • NF-kappa B
  • NFKBIA protein, human
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha
  • Calcium