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.
Kravchenko
Vladimir V
VV
Department of Immunology and Microbial Sciences, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Kaufmann
Gunnar F
GF
Mathison
John C
JC
Scott
David A
DA
Katz
Alexander Z
AZ
Grauer
David C
DC
Lehmann
Mandy
M
Meijler
Michael M
MM
Janda
Kim D
KD
Ulevitch
Richard J
RJ
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