Glucocorticoids limit acute lung inflammation in concert with inflammatory stimuli by induction of SphK1
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Glucocorticoids limit acute lung inflammation in concert with inflammatory stimuli by induction of SphK1. / Vettorazzi, Sabine; Bode, Constantin; Dejager, Lien; Frappart, Lucien; Shelest, Ekaterina; Klaßen, Carina; Tasdogan, Alpaslan; Reichardt, Holger M; Libert, Claude; Schneider, Marion; Weih, Falk; Henriette Uhlenhaut, N; David, Jean-Pierre; Gräler, Markus; Kleiman, Anna; Tuckermann, Jan P.
in: NAT COMMUN, Jahrgang 6, 2015, S. 7796.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Glucocorticoids limit acute lung inflammation in concert with inflammatory stimuli by induction of SphK1
AU - Vettorazzi, Sabine
AU - Bode, Constantin
AU - Dejager, Lien
AU - Frappart, Lucien
AU - Shelest, Ekaterina
AU - Klaßen, Carina
AU - Tasdogan, Alpaslan
AU - Reichardt, Holger M
AU - Libert, Claude
AU - Schneider, Marion
AU - Weih, Falk
AU - Henriette Uhlenhaut, N
AU - David, Jean-Pierre
AU - Gräler, Markus
AU - Kleiman, Anna
AU - Tuckermann, Jan P
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
U2 - 10.1038/ncomms8796
DO - 10.1038/ncomms8796
M3 - SCORING: Journal article
C2 - 26183376
VL - 6
SP - 7796
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
ER -