Modulation of gene expression via disruption of NF-kappaB signaling by a bacterial small molecule

Science. 2008 Jul 11;321(5886):259-63. doi: 10.1126/science.1156499. Epub 2008 Jun 19.

Abstract

The control of innate immune responses through activation of the nuclear transcription factor NF-kappaB is essential for the elimination of invading microbial pathogens. We showed that the bacterial N-(3-oxo-dodecanoyl) homoserine lactone (C12) selectively impairs the regulation of NF-kappaB functions in activated mammalian cells. The consequence is specific repression of stimulus-mediated induction of NF-kappaB-responsive genes encoding inflammatory cytokines and other immune regulators. These findings uncover a strategy by which C12-producing opportunistic pathogens, such as Pseudomonas aeruginosa, attenuate the innate immune system to establish and maintain local persistent infection in humans, for example, in cystic fibrosis patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Butyrolactone / analogs & derivatives*
  • 4-Butyrolactone / physiology
  • Adult
  • Animals
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cystic Fibrosis / microbiology
  • Female
  • Gene Expression Regulation*
  • Homoserine / analogs & derivatives*
  • Homoserine / physiology
  • Humans
  • I-kappa B Kinase / metabolism
  • I-kappa B Proteins / metabolism
  • Immunity, Innate
  • Interferon-gamma / immunology
  • Lipopolysaccharides / immunology
  • Macrophage Activation
  • Macrophages / immunology*
  • Macrophages / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Middle Aged
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • Phosphorylation
  • Pseudomonas Infections / immunology
  • Pseudomonas Infections / microbiology
  • Pseudomonas aeruginosa / immunology
  • Pseudomonas aeruginosa / pathogenicity*
  • Pseudomonas aeruginosa / physiology
  • Signal Transduction*
  • Toll-Like Receptors / metabolism
  • Transcription Factor RelA / metabolism

Substances

  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • I-kappa B Proteins
  • Lipopolysaccharides
  • N-(3-oxododecanoyl)homoserine lactone
  • NF-kappa B
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • Rela protein, mouse
  • Toll-Like Receptors
  • Transcription Factor RelA
  • NF-KappaB Inhibitor alpha
  • Homoserine
  • Interferon-gamma
  • I-kappa B Kinase
  • 4-Butyrolactone