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

Antony Adamson, Christopher Boddington, Polly Downton, William Rowe, James Bagnall, Connie Lam, Apolinar Maya-Mendoza, Lorraine Schmidt, Claire V Harper, David Spiller, David A. Rand, Dean Jackson, Michael R H White, Pawel Paszek

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number12057
JournalNature Communications
Volume7
DOIs
Publication statusPublished - 6 Jul 2016

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