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Glucocorticoids limit acute lung inflammation in concert with inflammatory stimuli by induction of SphK1

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  • Sabine Vettorazzi

    (Institute of Comparative Molecular Endocrinology (CME), Ulm University
    Leibniz Institute for Age Research – Fritz Lipmann Institute)

  • Constantin Bode

    (Molecular Cancer Research Centre (MKFZ), Charité – University Medical School (CVK))

  • Lien Dejager

    (Inflammation Research Center, Mouse Genetics in Inflammation group, VIB and University Ghent)

  • Lucien Frappart

    (Bat 10, HCL-Edouard Herriot Hospital, INSERM U590)

  • Ekaterina Shelest

    (Leibniz Institute for Natural Product Research and Infection Biology Hans Knöll Institute (HKI))

  • Carina Klaßen

    (Institute for Cellular and Molecular Immunology, University of Göttingen Medical School)

  • Alpaslan Tasdogan

    (Institute for Immunology, Ulm University)

  • Holger M. Reichardt

    (Institute for Cellular and Molecular Immunology, University of Göttingen Medical School)

  • Claude Libert

    (Inflammation Research Center, Mouse Genetics in Inflammation group, VIB and University Ghent)

  • Marion Schneider

    (Section of Experimental Anesthesiology, University Clinic Ulm)

  • Falk Weih

    (Leibniz Institute for Age Research – Fritz Lipmann Institute)

  • N. Henriette Uhlenhaut

    (Institute for Diabetes and Obesity, Helmholtz Zentrum München)

  • Jean-Pierre David

    (University Medical Center Hamburg-Eppendorf)

  • Markus Gräler

    (Molecular Cancer Research Centre (MKFZ), Charité – University Medical School (CVK)
    Center for Sepsis Control and Care (CSCC) and Center for Molecular Biomedicine (CMB), University Hospital Jena)

  • Anna Kleiman

    (Leibniz Institute for Age Research – Fritz Lipmann Institute
    Center for Sepsis Control and Care (CSCC) and Center for Molecular Biomedicine (CMB), University Hospital Jena)

  • Jan P. Tuckermann

    (Institute of Comparative Molecular Endocrinology (CME), Ulm University
    Leibniz Institute for Age Research – Fritz Lipmann Institute)

Abstract

Acute lung injury (ALI) is a severe inflammatory disease for which no specific treatment exists. As glucocorticoids have potent immunosuppressive effects, their application in ALI is currently being tested in clinical trials. However, the benefits of this type of regimen remain unclear. Here we identify a mechanism of glucocorticoid action that challenges the long-standing dogma of cytokine repression by the glucocorticoid receptor. Contrarily, synergistic gene induction of sphingosine kinase 1 (SphK1) by glucocorticoids and pro-inflammatory stimuli via the glucocorticoid receptor in macrophages increases circulating sphingosine 1-phosphate levels, which proves essential for the inhibition of inflammation. Chemical or genetic inhibition of SphK1 abrogates the therapeutic effects of glucocorticoids. Inflammatory p38 MAPK- and mitogen- and stress-activated protein kinase 1 (MSK1)-dependent pathways cooperate with glucocorticoids to upregulate SphK1 expression. Our findings support a critical role for SphK1 induction in the suppression of lung inflammation by glucocorticoids, and therefore provide rationales for effective anti-inflammatory therapies.

Suggested Citation

  • Sabine Vettorazzi & Constantin Bode & Lien Dejager & Lucien Frappart & Ekaterina Shelest & Carina Klaßen & Alpaslan Tasdogan & Holger M. Reichardt & Claude Libert & Marion Schneider & Falk Weih & N. H, 2015. "Glucocorticoids limit acute lung inflammation in concert with inflammatory stimuli by induction of SphK1," Nature Communications, Nature, vol. 6(1), pages 1-12, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8796
    DOI: 10.1038/ncomms8796
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    Cited by:

    1. Shih-Chang Hsu & Jer-Hwa Chang & Yuan-Pin Hsu & Kuan-Jen Bai & Shau-Ku Huang & Chin-Wang Hsu, 2019. "Circulating sphingosine-1-phosphate as a prognostic biomarker for community-acquired pneumonia," PLOS ONE, Public Library of Science, vol. 14(5), pages 1-13, May.
    2. Giorgio Caratti & Ulrich Stifel & Bozhena Caratti & Ali J. M. Jamil & Kyoung-Jin Chung & Michael Kiehntopf & Markus H. Gräler & Matthias Blüher & Alexander Rauch & Jan P. Tuckermann, 2023. "Glucocorticoid activation of anti-inflammatory macrophages protects against insulin resistance," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Tony Marion & Husni Elbahesh & Paul G Thomas & John P DeVincenzo & Richard Webby & Klaus Schughart, 2016. "Respiratory Mucosal Proteome Quantification in Human Influenza Infections," PLOS ONE, Public Library of Science, vol. 11(4), pages 1-16, April.

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