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


ABSTRACT: Cells respond dynamically to pulsatile cytokine stimulation. Here we report that single, or well-spaced pulses of TNF? (>100?min apart) give a high probability of NF-?B 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-?B system negative feedback protein A20. If a second pulse within the refractory phase is IL-1? instead of TNF?, 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-?B-dependent target gene activation. These data suggest that refractory states in the NF-?B system constitute an inherent design motif of the inflammatory response and we suggest that this may avoid harmful homogenous cellular activation.

SUBMITTER: Adamson A 

PROVIDER: S-EPMC4935804 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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

Adamson Antony A   Boddington Christopher C   Downton Polly P   Rowe William W   Bagnall James J   Lam Connie C   Maya-Mendoza Apolinar A   Schmidt Lorraine L   Harper Claire V CV   Spiller David G DG   Rand David A DA   Jackson Dean A DA   White Michael R H MR   Paszek Pawel P  

Nature communications 20160706


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 w  ...[more]

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