title: A specific sphingosine kinase 1 inhibitor attenuates airway hyperresponsiveness and inflammation in a mast cell-dependent murine model of allergic asthma.
abstract: BACKGROUND
  Sphingosine-1-phosphate (S1P), which is produced by 2 sphingosine kinase (SphK) isoenzymes, SphK1 and SphK2, has been implicated in IgE-mediated mast cell responses. However, studies of allergic inflammation in isotype-specific SphK knockout mice have not clarified their contribution, and the role that S1P plays in vivo in a mast cell- and IgE-dependent murine model of allergic asthma has not yet been examined.
  
  
  OBJECTIVE
  We used an isoenzyme-specific SphK1 inhibitor, SK1-I, to investigate the contributions of S1P and SphK1 to mast cell-dependent airway hyperresponsiveness (AHR) and airway inflammation in mice.
  
  
  METHODS
  Allergic airway inflammation and AHR were examined in a mast cell-dependent murine model of ovalbumin (OVA)-induced asthma. C57BL/6 mice received intranasal delivery of SK1-I before sensitization and challenge with OVA or only before challenge.
  
  
  RESULTS
  SK1-I inhibited antigen-dependent activation of human and murine mast cells and suppressed activation of nuclear factor κB (NF-κB), a master transcription factor that regulates the expression of proinflammatory cytokines. SK1-I treatment of mice sensitized to OVA in the absence of adjuvant, in which mast cell-dependent allergic inflammation develops, significantly reduced OVA-induced AHR to methacholine; decreased numbers of eosinophils and levels of the cytokines IL-4, IL-5, IL-6, IL-13, IFN-γ, and TNF-α and the chemokines eotaxin and CCL2 in bronchoalveolar lavage fluid; and decreased pulmonary inflammation, as well as activation of NF-κB in the lungs.
  
  
  CONCLUSIONS
  S1P and SphK1 play important roles in mast cell-dependent, OVA-induced allergic inflammation and AHR, in part by regulating the NF-κB pathway.
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Va 23298-0614, USA.
authors.forename: Megan M
authors.initials: MM
authors.lastname: Price
authors.forename: Carole A
authors.initials: CA
authors.lastname: Oskeritzian
authors.forename: Yves T
authors.initials: YT
authors.lastname: Falanga
authors.forename: Kuzhuvelil B
authors.initials: KB
authors.lastname: Harikumar
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Allegood
authors.forename: Sergio E
authors.initials: SE
authors.lastname: Alvarez
authors.forename: Daniel
authors.initials: D
authors.lastname: Conrad
authors.forename: John J
authors.initials: JJ
authors.lastname: Ryan
authors.forename: Sheldon
authors.initials: S
authors.lastname: Milstien
authors.forename: Sarah
authors.initials: S
authors.lastname: Spiegel
mesh_terms: D000605:Amino Alcohols / Q000494:pharmacology*; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D005260:Female; D020397:Goblet Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia / Q000188:drug therapy / Q000378:metabolism; D007073:Immunoglobulin E / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D010047:Ovalbumin / Q000494:pharmacology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D000605:Amino Alcohols; D018932:Chemokine CCL2; D007073:Immunoglobulin E; D007371:Interferon-gamma; D007378:Interleukins; D008246:Lysophospholipids; D016210:Methacholine Chloride; D016328:NF-kappa B; D010047:Ovalbumin; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D014409:Tumor Necrosis Factor-alpha; D000099157:Sphingosine Kinase; C111835:CCL2 protein, human; C544832:N-methyl-5-(4'-pentylphenyl)-2-aminopent-4-ene-1,3-diol; C060506:sphingosine 1-phosphate