Regulation of peroxisome proliferator-activated receptor β/δ expression and activity levels by toll-like receptor agonists and MAP kinase inhibitors in rat astrocytes

Authors

  • Dmitry V. Chistyakov,

    1. Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Institut für Neurobiochemie, Magdeburg, Germany
    2. Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, Russia
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  • Stepan Aleshin,

    1. Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Institut für Neurobiochemie, Magdeburg, Germany
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  • Marina G. Sergeeva,

    Corresponding author
    1. Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, Russia
    • Address correspondence and reprint requests to Prof Dr Georg Reiser, Otto-von-Guericke-Universitaet Magdeburg, Medizinische Fakultät, Institut für Neurobiochemie, Leipziger Strasse 44, D-39120, Magdeburg, Germany. E-mail: georg.reiser@med.ovgu.de

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  • Georg Reiser

    Corresponding author
    1. Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Institut für Neurobiochemie, Magdeburg, Germany
    • Address correspondence and reprint requests to Prof Dr Georg Reiser, Otto-von-Guericke-Universitaet Magdeburg, Medizinische Fakultät, Institut für Neurobiochemie, Leipziger Strasse 44, D-39120, Magdeburg, Germany. E-mail: georg.reiser@med.ovgu.de

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Abstract

Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is a potential regulator of neuroinflammation. Toll-like receptors (TLR) are innate immunity-related receptors of inflammatory stimuli. In the present report, we evaluate the molecular mechanisms of regulation of mRNA, protein, and transcriptional activity levels of PPARβ/δ by agonists of TLR4, TLR1/2, and TLR5, using lipopolysaccharide (LPS), peptidoglycan, and flagellin, respectively. We found that these stimuli increase the PPARβ/δ levels in astrocytes. Expression and activity of PPARβ/δ are separately regulated by inhibitors of p38, MEK1/2, extracellular signal-regulated kinases 1/2, and c-Jun N-terminal Kinase mitogen-activated protein kinases. The LPS-induced kinetics of PPARβ/δ expression is similar to that of the proinflammatory gene cyclooxygenase 2. Moreover, for both genes the expression depends on nuclear factor kappa-light-chain-enhancer of activated B cells and p38, and is induced after inhibition of protein synthesis. The up-regulation of the expression after inhibition of protein synthesis signifies the participation of a labile protein in regulation of PPARβ/δ expression. In contrast to cyclooxygenase 2, the cycloheximide-sensitive PPARβ/δ expression was not responsive to nuclear factor kappa-light-chain-enhancer of activated B cells inhibition. Measurements of PPARβ/δ mRNA stability showed that the PPARβ/δ mRNA levels are regulated post-transcriptionally. We found that in LPS-stimulated astrocytes, the half-life of PPARβ/δ mRNA was 50 min. Thus, we demonstrate that PPARβ/δ expression and activity are regulated in TLR agonist-stimulated astrocytes by mechanisms that are widely used for regulation of proinflammatory genes.

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Protein expression level of nuclear receptor PPARβ/δ is important for functions of this transcription factor. We investigate the regulatory mechanisms of PPARβ/δ in rat primary astrocytes stimulated by agonists of toll-like receptors (TLR): TLR4, TLR1/2, and TLR5. Expression, activity, mRNA stability, and superinduction of PPARβ/δ were up-regulated after TLR stimulation. These processes are sensitive to MAPKs and NF-kB inhibitors. Superinduction is up-regulation of mRNA expression after inhibition of protein synthesis.

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