Epigenetic regulation of pro-inflammatory cytokine secretion by sphingosine 1-phosphate (S1P) in acute lung injury: Role of S1P lyase

Adv Biol Regul. 2017 Jan:63:156-166. doi: 10.1016/j.jbior.2016.09.007. Epub 2016 Sep 29.


Cellular level of sphingosine-1-phosphate (S1P), the simplest bioactive sphingolipid, is tightly regulated by its synthesis catalyzed by sphingosine kinases (SphKs) 1 & 2 and degradation mediated by S1P phosphatases, lipid phosphate phosphatases, and S1P lyase. The pleotropic actions of S1P are attributed to its unique inside-out (extracellular) signaling via G-protein-coupled S1P1-5 receptors, and intracellular receptor independent signaling. Additionally, S1P generated in the nucleus by nuclear SphK2 modulates HDAC1/2 activity, regulates histone acetylation, and transcription of pro-inflammatory genes. Here, we present data on the role of S1P lyase mediated S1P signaling in regulating LPS-induced inflammation in lung endothelium. Blocking S1P lyase expression or activity attenuated LPS-induced histone acetylation and secretion of pro-inflammatory cytokines. Degradation of S1P by S1P lyase generates Δ2-hexadecenal and ethanolamine phosphate and the long-chain fatty aldehyde produced in the cytoplasmic compartment of the endothelial cell seems to modulate histone acetylation pattern, which is different from the nuclear SphK2/S1P signaling and inhibition of HDAC1/2. These in vitro studies suggest that S1P derived long-chain fatty aldehyde may be an epigenetic regulator of pro-inflammatory genes in sepsis-induced lung inflammation. Trapping fatty aldehydes and other short chain aldehydes such as 4-hydroxynonenal derived from S1P degradation and lipid peroxidation, respectively by cell permeable agents such as phloretin or other aldehyde trapping agents may be useful in treating sepsis-induced lung inflammation via modulation of histone acetylation. .

Keywords: Acute lung injury; Hexadecenal; Histone acetylation; Histone deacetylases; S1P lyase; S1P signaling; Sphingosine kinases.

Publication types

  • Review

MeSH terms

  • Acetylation
  • Acute Lung Injury / chemically induced
  • Acute Lung Injury / genetics*
  • Acute Lung Injury / metabolism
  • Acute Lung Injury / pathology
  • Aldehyde-Lyases / genetics*
  • Aldehyde-Lyases / metabolism
  • Aldehydes / metabolism
  • Animals
  • Cytokines / genetics
  • Cytokines / metabolism*
  • Epigenesis, Genetic*
  • Histone Deacetylase 1 / genetics
  • Histone Deacetylase 1 / metabolism
  • Histone Deacetylase 2 / genetics
  • Histone Deacetylase 2 / metabolism
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Lipopolysaccharides
  • Lysophospholipids / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphoric Monoester Hydrolases / metabolism
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Receptors, Lysosphingolipid / genetics
  • Receptors, Lysosphingolipid / metabolism
  • Signal Transduction
  • Sphingosine / analogs & derivatives*
  • Sphingosine / metabolism


  • Aldehydes
  • Cytokines
  • Histones
  • Lipopolysaccharides
  • Lysophospholipids
  • Membrane Proteins
  • Receptors, Lysosphingolipid
  • sphingosine 1-phosphate
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • sphingosine kinase 2, human
  • sphingosine-1-phosphate phosphatase
  • Phosphoric Monoester Hydrolases
  • HDAC1 protein, human
  • HDAC2 protein, human
  • Histone Deacetylase 1
  • Histone Deacetylase 2
  • Aldehyde-Lyases
  • SGPL1 protein, human
  • 4-hydroxy-2-nonenal
  • Sphingosine