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Oscillation of p38 activity controls efficient pro-inflammatory gene expression

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  • Taichiro Tomida

    (Institute of Medical Science, The University of Tokyo
    Present address: Department of Physiology, School of Medicine, Toho University, 5-21-16 Omori-Nishi, Ota-ku, Tokyo 143-8540, Japan.)

  • Mutsuhiro Takekawa

    (Institute of Medical Science, The University of Tokyo)

  • Haruo Saito

    (Institute of Medical Science, The University of Tokyo)

Abstract

The p38 MAP kinase signalling pathway controls inflammatory responses and is an important target of anti-inflammatory drugs. Although pro-inflammatory cytokines such as interleukin-1β (IL-1β) appear to induce only transient activation of p38 (over ∼60 min), longer cytokine exposure is necessary to induce p38-dependent effector genes. Here we study the dynamics of p38 activation in individual cells using a Förster resonance energy transfer (FRET)-based p38 activity reporter. We find that, after an initial burst of activity, p38 MAPK activity subsequently oscillates for more than 8 h under continuous IL-1β stimulation. However, as this oscillation is asynchronous, the measured p38 activity population average is only slightly higher than basal level. Mathematical modelling, which we have experimentally verified, indicates that the asynchronous oscillation of p38 is generated through a negative feedback loop involving the dual-specificity phosphatase MKP-1/DUSP1. We find that the oscillatory p38 activity is necessary for efficient expression of pro-inflammatory genes such as IL-6, IL-8 and COX-2.

Suggested Citation

  • Taichiro Tomida & Mutsuhiro Takekawa & Haruo Saito, 2015. "Oscillation of p38 activity controls efficient pro-inflammatory gene expression," Nature Communications, Nature, vol. 6(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9350
    DOI: 10.1038/ncomms9350
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    Cited by:

    1. Yuliia Didan & Milad Ghomlaghi & Lan K. Nguyen & Dominic C. H. Ng, 2024. "Stress pathway outputs are encoded by pH-dependent clustering of kinase components," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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