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Vettorazzi, S.* ; Bode, C.* ; Dejager, L.* ; Frappart, L.* ; Shelest, E.* ; Klaßen, C.* ; Tasdogan, A.* ; Reichardt, H.M.* ; Libert, C.* ; Schneider, M.* ; Weih, F.* ; Uhlenhaut, N.H. ; David, J.P.* ; Gräler, M.H.* ; Kleiman, A.* ; Tuckermann, J.P.*

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

Nat. Commun. 6:7796 (2015)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Respiratory-distress-syndrome; P38 Map Kinase; Sphingosine 1-phosphate; In-vivo; Receptor Dimerization; Multiple-sclerosis; Barrier Integrity; Gene-expression; Mouse Models; Injury
Language english
Publication Year 2015
HGF-reported in Year 2015
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 6, Issue: , Pages: , Article Number: 7796 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Cancer (IDC)
POF-Topic(s) 90000 - German Center for Diabetes Research
Research field(s) Helmholtz Diabetes Center
PSP Element(s) G-501900-227
PubMed ID 26183376
DOI 10.1038/ncomms8796
WOS ID WOS:000358860000004
Erfassungsdatum 2015-07-19
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