title: Sphingosine kinase: a point of convergence in the action of diverse neutrophil priming agents.
abstract: Neutrophils are a vital component of the early acute inflammatory response, but can cause profound tissue damage when activated to excess or prevented from undergoing apoptosis. However, much remains unknown about the intracellular signaling pathways regulating neutrophil activity. The structurally diverse neutrophil-priming agents platelet-activating factor, TNF-alpha, and the substance P analog [D-Arg(6), D-Trp(7,9),N(me)Phe(8)]-substance P(6-11) (SP-G) stimulated a rapid increase in sphingosine kinase activity in freshly isolated human neutrophils. This activity was blocked by preincubation with the sphingosine kinase inhibitor N,N-dimethylsphingosine (DMS). DMS also inhibited the increase in intracellular calcium concentration stimulated by platelet-activating factor, fMLP, and SP-G. This suggests that the increase in intracellular calcium concentration by these agents is dependent on sphingosine kinase activation and the generation of sphingosine-1-phosphate. Changes in cell polarization and the augmentation of the fMLP-induced superoxide anion generation, by all priming agents were also inhibited by DMS, while only the superoxide anion release was blocked by the phosphatidylinositol 3-kinase inhibitor LY294002. Moreover, SP-G and GM-CSF inhibited constitutive neutrophil apoptosis which was completely blocked by DMS. These results suggest a novel role for sphingosine kinase in the regulation of neutrophil priming.
authors.affiliation: Lung Inflammatory Group, Center for Inflammation Research, University of Edinburgh, United Kingdom. a.mackinnon@ed.ac.uk
authors.forename: Alison C
authors.initials: AC
authors.lastname: MacKinnon
authors.forename: Avril
authors.initials: A
authors.lastname: Buckley
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Chilvers
authors.forename: Adriano G
authors.initials: AG
authors.lastname: Rossi
authors.forename: Christopher
authors.initials: C
authors.lastname: Haslett
authors.forename: Tariq
authors.initials: T
authors.lastname: Sethi
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D020013:Calcium Signaling / Q000187:drug effects; D016764:Cell Polarity / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D009025:Morpholines / Q000494:pharmacology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D010446:Peptide Fragments / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000494:pharmacology; D011994:Recombinant Proteins; D016897:Respiratory Burst / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013373:Substance P / Q000031:analogs & derivatives* / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000099157:Sphingosine Kinase
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D009025:Morpholines; D009240:N-Formylmethionine Leucyl-Phenylalanine; D010446:Peptide Fragments; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor); D010972:Platelet Activating Factor; D011994:Recombinant Proteins; D013110:Sphingosine; D013373:Substance P; D013481:Superoxides; D014409:Tumor Necrosis Factor-alpha; D000099157:Sphingosine Kinase; C046958:substance P (6-11), Arg(6)-Trp(7,9)-Me-Phe(8)-; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C061800:N,N-dimethylsphingosine