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Sci. Signal., 20 October 2009
Vol. 2, Issue 93, p. ra65
[DOI: 10.1126/scisignal.2000599]

RESEARCH ARTICLES

A Noisy Paracrine Signal Determines the Cellular NF-{kappa}B Response to Lipopolysaccharide

Timothy K. Lee1, Elissa M. Denny1, Jayodita C. Sanghvi1, Jahlionais E. Gaston2, Nathaniel D. Maynard1, Jacob J. Hughey1, and Markus W. Covert1*

1 Bioengineering Department, Stanford University, 318 Campus Drive West, Stanford, CA 94305–5444, USA.
2 Division of Biology, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125, USA.

Abstract: Nearly identical cells can exhibit substantially different responses to the same stimulus. We monitored the nuclear localization dynamics of nuclear factor {kappa}B (NF-{kappa}B) in single cells stimulated with tumor necrosis factor–{alpha} (TNF-{alpha}) and lipopolysaccharide (LPS). Cells stimulated with TNF-{alpha} have quantitative differences in NF-{kappa}B nuclear localization, whereas LPS-stimulated cells can be clustered into transient or persistent responders, representing two qualitatively different groups based on the NF-{kappa}B response. These distinct behaviors can be linked to a secondary paracrine signal secreted at low concentrations, such that not all cells undergo a second round of NF-{kappa}B activation. From our single-cell data, we built a computational model that captures cell variability, as well as population behaviors. Our findings show that mammalian cells can create "noisy" environments to produce diversified responses to stimuli.

* To whom correspondence should be addressed. E-mail: mcovert{at}stanford.edu

Citation: T. K. Lee, E. M. Denny, J. C. Sanghvi, J. E. Gaston, N. D. Maynard, J. J. Hughey, M. W. Covert, A Noisy Paracrine Signal Determines the Cellular NF-{kappa}B Response to Lipopolysaccharide. Sci. Signal. 2, ra65 (2009).

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