title: Glucocorticoids limit acute lung inflammation in concert with inflammatory stimuli by induction of SphK1.
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.
authors.affiliation: Institute of Comparative Molecular Endocrinology (CME), Ulm University, 89081 Ulm, Germany.|Leibniz Institute for Age Research - Fritz Lipmann Institute, 07745 Jena, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Vettorazzi
authors.affiliation: Molecular Cancer Research Centre (MKFZ), Charité - University Medical School (CVK), 13353 Berlin, Germany.
authors.forename: Constantin
authors.initials: C
authors.lastname: Bode
authors.affiliation: Inflammation Research Center, Mouse Genetics in Inflammation group, VIB and University Ghent, B9052 Ghent, Belgium.
authors.forename: Lien
authors.initials: L
authors.lastname: Dejager
authors.affiliation: Department of Pathology, Bat 10, HCL-Edouard Herriot Hospital, INSERM U590, 69437 Lyon, France.
authors.forename: Lucien
authors.initials: L
authors.lastname: Frappart
authors.affiliation: Leibniz Institute for Natural Product Research and Infection Biology Hans Knöll Institute (HKI), 07745 Jena, Germany.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Shelest
authors.affiliation: Institute for Cellular and Molecular Immunology, University of Göttingen Medical School, 37073 Göttingen, Germany.
authors.forename: Carina
authors.initials: C
authors.lastname: Klaßen
authors.affiliation: Institute for Immunology, Ulm University, 89081 Ulm, Germany.
authors.forename: Alpaslan
authors.initials: A
authors.lastname: Tasdogan
authors.affiliation: Institute for Cellular and Molecular Immunology, University of Göttingen Medical School, 37073 Göttingen, Germany.
authors.forename: Holger M
authors.initials: HM
authors.lastname: Reichardt
authors.affiliation: Inflammation Research Center, Mouse Genetics in Inflammation group, VIB and University Ghent, B9052 Ghent, Belgium.
authors.forename: Claude
authors.initials: C
authors.lastname: Libert
authors.affiliation: Section of Experimental Anesthesiology, University Clinic Ulm, 89081 Ulm, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Schneider
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute, 07745 Jena, Germany.
authors.forename: Falk
authors.initials: F
authors.lastname: Weih
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz Zentrum München, 85748 Garching, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Henriette Uhlenhaut
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: David
authors.affiliation: Molecular Cancer Research Centre (MKFZ), Charité - University Medical School (CVK), 13353 Berlin, Germany.|Department of Anesthesiology and Intensive Care Medicine, Center for Sepsis Control and Care (CSCC) and Center for Molecular Biomedicine (CMB), University Hospital Jena, 07740 Jena, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Gräler
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute, 07745 Jena, Germany.|Department of Anesthesiology and Intensive Care Medicine, Center for Sepsis Control and Care (CSCC) and Center for Molecular Biomedicine (CMB), University Hospital Jena, 07740 Jena, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Kleiman
authors.affiliation: Institute of Comparative Molecular Endocrinology (CME), Ulm University, 89081 Ulm, Germany.|Leibniz Institute for Age Research - Fritz Lipmann Institute, 07745 Jena, Germany.
authors.forename: Jan P
authors.initials: JP
authors.lastname: Tuckermann
mesh_terms: D055371:Acute Lung Injury / Q000276:immunology*; D000818:Animals; D047369:Chromatin Immunoprecipitation; D016207:Cytokines / Q000187:drug effects / Q000276:immunology; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D007249:Inflammation; D008246:Lysophospholipids / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000187:drug effects* / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011965:Receptors, Glucocorticoid / Q000819:agonists*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000276:immunology; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology; D000099157:Sphingosine Kinase
chemical_list: D016207:Cytokines; D005938:Glucocorticoids; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D011965:Receptors, Glucocorticoid; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D013110:Sphingosine; D048051:p38 Mitogen-Activated Protein Kinases; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate; C116919:mitogen and stress-activated protein kinase 1