A noisy paracrine signal determines the cellular NF-kappaB response to lipopolysaccharide.
Nearly identical cells can exhibit substantially different responses to the same stimulus. We monitored the nuclear localization dynamics of nuclear factor kappaB (NF-kappaB) in single cells stimulated with tumor necrosis factor-alpha (TNF-alpha) and lipopolysaccharide (LPS). Cells stimulated with TNF-alpha have quantitative differences in NF-kappaB nuclear localization, whereas LPS-stimulated cells can be clustered into transient or persistent responders, representing two qualitatively different groups based on the NF-kappaB 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-kappaB 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.
Lee
Timothy K
TK
Bioengineering Department, Stanford University, 318 Campus Drive West, Stanford, CA 94305-5444, USA.
Denny
Elissa M
EM
Sanghvi
Jayodita C
JC
Gaston
Jahlionais E
JE
Maynard
Nathaniel D
ND
Hughey
Jacob J
JJ
Covert
Markus W
MW
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D018920:Coculture Techniques; D008070:Lipopolysaccharides / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D019899:Paracrine Communication; D010641:Phenotype; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha