Research ArticleCOMPUTATIONAL BIOLOGY

A Noisy Paracrine Signal Determines the Cellular NF-κB Response to Lipopolysaccharide

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Science Signaling  20 Oct 2009:
Vol. 2, Issue 93, pp. ra65
DOI: 10.1126/scisignal.2000599

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Prolonging NF-κB Activation

Regulation of the activity of the transcription factor NF-κB, which plays key roles in immune responses, exhibits complicated cellular dynamics. Tumor necrosis factor–α (TNF-α), a proinflammatory cytokine that activates the death-domain receptor TNFR, and lipopolysaccharide (LPS), a pathogen-derived molecule that activates the Toll-like receptor TLR4, both activate NF-κB. Lee et al. provide a mechanism by which cells respond to these two ligands with different kinetics. Cells responding to TNF-α exhibit an oscillating translocation of NF-κB in and out of the nucleus, with all cells responding similarly. In contrast, cells responding to LPS showed two distinct modes, with one population exhibiting transient nuclear localization of NF-κB and a second exhibiting persistent nuclear localization. Lee et al. modified an existing computational model of the pathways that activate NF-κB and found that cells responding to LPS produce TNF-α in concentrations that are low enough that only a subset of neighboring cells responds. This paracrine TNF-α signal produces the population of LPS-responsive cells with persistent prolonged NF-κB activation.

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