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 G Spiller, David A Rand, Dean A Jackson, Michael R H White, Pawel Paszek

Research output: Contribution to journalArticle

32 Citations (Scopus)
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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
Pages (from-to)12057
JournalNature Communications
Volume7
Early online date6 Jul 2016
DOIs
Publication statusPublished - 6 Jul 2016

Keywords

  • Cell Line, Tumor
  • Feedback, Physiological
  • Gene Expression Regulation
  • Genes, Reporter
  • Green Fluorescent Proteins/genetics
  • Humans
  • I-kappa B Kinase/genetics
  • Interleukin-1beta/pharmacology
  • Luminescent Proteins/genetics
  • NF-KappaB Inhibitor alpha/genetics
  • NF-kappa B/genetics
  • Neurons
  • RNA, Small Interfering/genetics
  • Receptors, Tumor Necrosis Factor, Type I/genetics
  • Recombinant Fusion Proteins/genetics
  • Signal Transduction/immunology
  • Tumor Necrosis Factor alpha-Induced Protein 3/antagonists & inhibitors
  • Tumor Necrosis Factor-alpha/pharmacology

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  • Cite this

    Adamson, A., Boddington, C., Downton, P., Rowe, W., Bagnall, J., Lam, C., Maya-Mendoza, A., Schmidt, L., Harper, C. V., Spiller, D. G., Rand, D. A., Jackson, D. A., White, M. R. H., & Paszek, P. (2016). Signal transduction controls heterogeneous NF-κB dynamics and target gene expression through cytokine-specific refractory states. Nature Communications, 7, 12057. [12057]. https://doi.org/10.1038/ncomms12057