Modulation of gene expression via disruption of NF-kappaB signaling by a bacterial small molecule.
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.
Department of Immunology and Microbial Sciences, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Vladimir V
VV
Kravchenko
Gunnar F
GF
Kaufmann
John C
JC
Mathison
David A
DA
Scott
Alexander Z
AZ
Katz
David C
DC
Grauer
Mandy
M
Lehmann
Michael M
MM
Meijler
Kim D
KD
Janda
Richard J
RJ
Ulevitch
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000502:physiology; D000328:Adult; D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003550:Cystic Fibrosis / Q000382:microbiology; D005260:Female; D005786:Gene Expression Regulation; D006714:Homoserine / Q000031:analogs & derivatives* / Q000502:physiology; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011552:Pseudomonas Infections / Q000276:immunology / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000276:immunology / Q000472:pathogenicity* / Q000502:physiology; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism
C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; C109860:N-(3-oxododecanoyl)homoserine lactone; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; C498144:Rela protein, mouse; D051193:Toll-Like Receptors; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D006714:Homoserine; D007371:Interferon-gamma; D051550:I-kappa B Kinase; D015107:4-Butyrolactone