Temperature regulates NF-κB dynamics and function through timing of A20 transcription

C V Harper, D J Woodcock, C Lam, M Garcia-Albornoz, A Adamson, L Ashall, W Rowe, P Downton, L Schmidt, S West, D G Spiller, D A Rand, M R H White

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Abstract

NF-κB signaling plays a pivotal role in control of the inflammatory response. We investigated how the dynamics and function of NF-κB were affected by temperature within the mammalian physiological range (34 °C to 40 °C). An increase in temperature led to an increase in NF-κB nuclear/cytoplasmic oscillation frequency following Tumor Necrosis Factor alpha (TNFα) stimulation. Mathematical modeling suggested that this temperature sensitivity might be due to an A20-dependent mechanism, and A20 silencing removed the sensitivity to increased temperature. The timing of the early response of a key set of NF-κB target genes showed strong temperature dependence. The cytokine-induced expression of many (but not all) later genes was insensitive to temperature change (suggesting that they might be functionally temperature-compensated). Moreover, a set of temperature- and TNFα-regulated genes were implicated in NF-κB cross-talk with key cell-fate-controlling pathways. In conclusion, NF-κB dynamics and target gene expression are modulated by temperature and can accurately transmit multidimensional information to control inflammation.

Original languageEnglish
Pages (from-to)E5243-E5249
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number22
Early online date14 May 2018
DOIs
Publication statusPublished - 29 May 2018

Keywords

  • Animals
  • Cell Line, Tumor
  • Cells, Cultured
  • Cytokines/metabolism
  • Gene Expression Regulation/genetics
  • Gene Knockdown Techniques
  • Humans
  • Inflammation
  • Mice
  • NF-kappa B/genetics
  • Signal Transduction/genetics
  • Temperature
  • Tumor Necrosis Factor alpha-Induced Protein 3/analysis
  • Tumor Necrosis Factor-alpha/metabolism

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  • Cite this

    Harper, C. V., Woodcock, D. J., Lam, C., Garcia-Albornoz, M., Adamson, A., Ashall, L., Rowe, W., Downton, P., Schmidt, L., West, S., Spiller, D. G., Rand, D. A., & White, M. R. H. (2018). Temperature regulates NF-κB dynamics and function through timing of A20 transcription. Proceedings of the National Academy of Sciences of the United States of America, 115(22), E5243-E5249. https://doi.org/10.1073/pnas.1803609115