title: Oscillation of p38 activity controls efficient pro-inflammatory gene expression.
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.
authors.affiliation: Division of Molecular Cell Signaling, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Taichiro
authors.initials: T
authors.lastname: Tomida
authors.affiliation: Division of Cell Signaling and Molecular Medicine, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Mutsuhiro
authors.identifier: http://orcid.org/0000-0002-8027-3847
authors.initials: M
authors.lastname: Takekawa
authors.affiliation: Division of Molecular Cell Signaling, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Haruo
authors.initials: H
authors.lastname: Saito
mesh_terms: D003198:Computer Simulation; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1 / Q000187:drug effects / Q000378:metabolism*; D025461:Feedback, Physiological; D031541:Fluorescence Resonance Energy Transfer; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D007249:Inflammation / Q000235:genetics; D053583:Interleukin-1beta / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D016209:Interleukin-8 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D059008:Time-Lapse Imaging; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*
chemical_list: C508606:CXCL8 protein, human; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D012333:RNA, Messenger; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D048051:p38 Mitogen-Activated Protein Kinases; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1