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Science 309 (5742): 1854-1857

Copyright © 2005 by the American Association for the Advancement of Science

Achieving Stability of Lipopolysaccharide-Induced NF-{kappa}B Activation

Markus W. Covert,* Thomas H. Leung,* Jahlionais E. Gaston, David Baltimore{dagger}

Abstract: The activation dynamics of the transcription factor NF-{kappa}B exhibit damped oscillatory behavior when cells are stimulated by tumor necrosis factor–{alpha} (TNF{alpha}) but stable behavior when stimulated by lipopolysaccharide (LPS). LPS binding to Toll-like receptor 4 (TLR4) causes activation of NF-{kappa}B that requires two downstream pathways, each of which when isolated exhibits damped oscillatory behavior. Computational modeling of the two TLR4-dependent signaling pathways suggests that one pathway requires a time delay to establish early anti-phase activation of NF-{kappa}B by the two pathways. The MyD88-independent pathway required Inferon regulatory factor 3–dependent expression of TNF{alpha} to activate NF-{kappa}B, and the time required for TNF{alpha} synthesis established the delay.

Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.

* These authors contributed equally to this work.

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

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