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

Sabine Vettorazzi, Constantin Bode, Lien Dejager, Lucien Frappart, Ekaterina Shelest, Carina Klaßen, Alpaslan Tasdogan, Holger M. Reichardt, Claude Libert, Marion Schneider, Falk Weih, N. Henriette Uhlenhaut, Jean-Pierre David, Markus Gräler, Anna Kleiman () and Jan P. Tuckermann ()
Additional contact information
Sabine Vettorazzi: Institute of Comparative Molecular Endocrinology (CME), Ulm University
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)
Anna Kleiman: Leibniz Institute for Age Research – Fritz Lipmann Institute
Jan P. Tuckermann: Institute of Comparative Molecular Endocrinology (CME), Ulm University

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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.

Date: 2015
References: Add references at CitEc
Citations: View citations in EconPapers (3)

Downloads: (external link)
https://www.nature.com/articles/ncomms8796 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8796

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms8796

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().