n-(3-oxododecanoyl)homoserine-lactone and Cystic-Fibrosis

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.

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