Bacterial induction of inducible nitric oxide synthase in cultured human intestinal epithelial cells

Gastroenterology. 1998 Jan;114(1):93-102. doi: 10.1016/s0016-5085(98)70637-7.


Background & aims: Enterocytes play a major role in the mucosa as a source of proinflammatory cytokines and cytotoxins. We tested the hypothesis that bacteria induce expression of the inducible nitric oxide synthase (iNOS) in cultured human enterocytes.

Methods: DLD-1 and Caco-2BBe cell monolayers exposed to Salmonella dublin were analyzed for iNOS up-regulation and nitric oxide production (NOx) in the presence of various proinflammatory cytokines.

Results: S. dublin augmented NOx in interferon gamma (IFN-gamma)-primed cells but had no independent effect on iNOS expression. S. dublin-induced NOx was not mediated by endotoxin and was augmented by an enteroinvasive phenotype. In DLD-1 cells, S. dublin-mediated NOx was blocked by inhibitors of nuclear factor kappa B (NF-kappa B) and tyrosine kinase activation and was steroid resistant. Cis-acting elements in the human iNOS promoter responsive to endotoxin and S. dublin stimulation of IFN-gamma-treated DLD-1 cells were identified between 10.9 and 8.7 kilobases upstream of the transcription initiation site.

Conclusions: S. dublin alters the regulation of iNOS messenger RNA in IFN-gamma-treated intestinal epithelial cells via a steroid-resistant pathway involving NF-kappa B and tyrosine kinase activity. Because bacterial interaction with cytokine-primed epithelial cells induces the synthesis of NO, an endogenous antimicrobial agent, these findings may have implications for the regulation of mucosal immunity.

MeSH terms

  • Cell Line
  • Humans
  • Interferon-gamma / pharmacology
  • Intestinal Mucosa / enzymology*
  • Intestinal Mucosa / microbiology*
  • Lipopolysaccharides / pharmacology
  • Nitric Oxide Synthase / biosynthesis*
  • Salmonella Infections / enzymology*
  • Salmonella*


  • Lipopolysaccharides
  • Interferon-gamma
  • Nitric Oxide Synthase