A Noisy Paracrine Signal Determines the Cellular NF-
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 
B (NF-B) in single cells stimulated with tumor necrosis factor–
(TNF-) and lipopolysaccharide (LPS). Cells stimulated with TNF- have quantitative differences in NF-B nuclear localization, whereas LPS-stimulated cells can be clustered into transient or persistent responders, representing two qualitatively different groups based on the NF-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-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
