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

Nat Commun. 2015 Jul 17;6:7796. doi: 10.1038/ncomms8796.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury / immunology*
  • Animals
  • Chromatin Immunoprecipitation
  • Cytokines / drug effects
  • Cytokines / immunology
  • Flow Cytometry
  • Gene Expression Regulation / drug effects
  • Glucocorticoids / pharmacology*
  • Inflammation
  • Lysophospholipids / metabolism
  • Macrophages / drug effects*
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • Phosphotransferases (Alcohol Group Acceptor) / drug effects*
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Real-Time Polymerase Chain Reaction
  • Receptors, Glucocorticoid / agonists*
  • Ribosomal Protein S6 Kinases, 90-kDa / immunology
  • Sphingosine / analogs & derivatives
  • Sphingosine / metabolism
  • Transcriptional Activation / drug effects
  • Up-Regulation
  • p38 Mitogen-Activated Protein Kinases / immunology

Substances

  • Cytokines
  • Glucocorticoids
  • Lysophospholipids
  • Receptors, Glucocorticoid
  • sphingosine 1-phosphate
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Ribosomal Protein S6 Kinases, 90-kDa
  • mitogen and stress-activated protein kinase 1
  • p38 Mitogen-Activated Protein Kinases
  • Sphingosine