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.
Bioengineering Department, Stanford University, 318 Campus Drive West, Stanford, CA 94305-5444, USA.
Timothy K
TK
Lee
Elissa M
EM
Denny
Jayodita C
JC
Sanghvi
Jahlionais E
JE
Gaston
Nathaniel D
ND
Maynard
Jacob J
JJ
Hughey
Markus W
MW
Covert
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