title: Epigenetic regulation of pro-inflammatory cytokine secretion by sphingosine 1-phosphate (S1P) in acute lung injury: Role of S1P lyase.
abstract: 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. .
authors.affiliation: Department of Biochemistry & Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Ebenezer
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Panfeng
authors.initials: P
authors.lastname: Fu
authors.affiliation: Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Vidyani
authors.initials: V
authors.lastname: Suryadevara
authors.affiliation: Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Yutong
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, USA; Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA. Electronic address: visnatar@uic.edu.
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Natarajan
mesh_terms: D000107:Acetylation; D055371:Acute Lung Injury / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000446:Aldehyde-Lyases / Q000235:genetics* / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides; D008246:Lysophospholipids / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D000446:Aldehyde-Lyases; D000447:Aldehydes; D016207:Cytokines; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006657:Histones; D008070:Lipopolysaccharides; D008246:Lysophospholipids; D008565:Membrane Proteins; D010744:Phosphoric Monoester Hydrolases; D017853:Phosphotransferases (Alcohol Group Acceptor); D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate; C000594250:sphingosine kinase 2, human; C401298:sphingosine-1-phosphate phosphatase; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human; C000623292:SGPL1 protein, human; C027576:4-hydroxy-2-nonenal
keywords: Acute lung injury; Hexadecenal; Histone acetylation; Histone deacetylases; S1P lyase; S1P signaling; Sphingosine kinases