Submitted on February 14, 2008
Accepted on June 6, 2008
Modulation of Gene Expression Via Disruption of NF-
B Signaling by a Bacterial Small Molecule
Vladimir V. Kravchenko 1, Gunnar F. Kaufmann 2, John C. Mathison 1, David A. Scott 1, Alexander Z. Katz 1, David C. Grauer 1, Mandy Lehmann 1, Michael M. Meijler 2, Kim D. Janda 3, Richard J. Ulevitch 1*
1 Department of Immunology and Microbial Sciences, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, California 92037, USA.
2 Department of Immunology and Microbial Sciences, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, California 92037, USA.; Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, California 92037, USA.; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, California 92037, USA.
3 Department of Immunology and Microbial Sciences, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, California 92037, USA.; Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, California 92037, USA.; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, California 92037, USA.; Worm Institute of Research and Medicine, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, California 92037, USA.
* To whom correspondence should be addressed.
Richard J. Ulevitch , E-mail: ulevitch{at}scripps.edu
The control of innate immune responses through activation of the transcription factor NF-
B is essential for elimination of invading microbial pathogens. We demonstrate that the bacterial N-(3-oxo-dodecanoyl) homoserine lactone (C12) selectively impairs the regulation of NF-B functions in activated mammalian cells. The consequence is specific repression of stimulus-mediated induction of NF-B-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.
