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


Editor's Summary

Prolonging NF-{kappa}B Activation
Regulation of the activity of the transcription factor NF-{kappa}B, which plays key roles in immune responses, exhibits complicated cellular dynamics. Tumor necrosis factor–{alpha} (TNF-{alpha}), 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-{kappa}B. Lee et al. provide a mechanism by which cells respond to these two ligands with different kinetics. Cells responding to TNF-{alpha} exhibit an oscillating translocation of NF-{kappa}B 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-{kappa}B and a second exhibiting persistent nuclear localization. Lee et al. modified an existing computational model of the pathways that activate NF-{kappa}B and found that cells responding to LPS produce TNF-{alpha} in concentrations that are low enough that only a subset of neighboring cells responds. This paracrine TNF-{alpha} signal produces the population of LPS-responsive cells with persistent prolonged NF-{kappa}B activation.

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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