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Nat Commun. 2016 Jul 6;7:12057. doi: 10.1038/ncomms12057.

Signal transduction controls heterogeneous NF-κB dynamics and target gene expression through cytokine-specific refractory states.

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Systems Microscopy Centre, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
The Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.
Warwick Systems Biology and Mathematics Institute, University of Warwick, Coventry CV4 7AL, UK.


Cells respond dynamically to pulsatile cytokine stimulation. Here we report that single, or well-spaced pulses of TNFα (>100 min apart) give a high probability of NF-κB activation. However, fewer cells respond to shorter pulse intervals (<100 min) suggesting a heterogeneous refractory state. This refractory state is established in the signal transduction network downstream of TNFR and upstream of IKK, and depends on the level of the NF-κB system negative feedback protein A20. If a second pulse within the refractory phase is IL-1β instead of TNFα, all of the cells respond. This suggests a mechanism by which two cytokines can synergistically activate an inflammatory response. Gene expression analyses show strong correlation between the cellular dynamic response and NF-κB-dependent target gene activation. These data suggest that refractory states in the NF-κB system constitute an inherent design motif of the inflammatory response and we suggest that this may avoid harmful homogenous cellular activation.

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