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Science 321 (5886): 259-263

Copyright © 2008 by the American Association for the Advancement of Science

Modulation of Gene Expression via Disruption of NF-{kappa}B Signaling by a Bacterial Small Molecule

Vladimir V. Kravchenko,1 Gunnar F. Kaufmann,1,2,3 John C. Mathison,1 David A. Scott,1 Alexander Z. Katz,1 David C. Grauer,1 Mandy Lehmann,1 Michael M. Meijler,1,2,3* Kim D. Janda,1,2,3,4 Richard J. Ulevitch1{dagger}

Abstract: The control of innate immune responses through activation of the nuclear transcription factor NF-{kappa}B 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-{kappa}B functions in activated mammalian cells. The consequence is specific repression of stimulus-mediated induction of NF-{kappa}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.

1 Department of Immunology and Microbial Sciences, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
2 Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
3 The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
4 Worm Institute of Research and Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA92037, USA.

* Present address: Department of Chemistry, Ben-Gurion University of Negev, Be'er Sheva, Israel.

{dagger} To whom correspondence should be addressed. E-mail: ulevitch{at}scripps.edu


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