title: Human Platelets Utilize Cycloxygenase-1 to Generate Dioxolane A3, a Neutrophil-activating Eicosanoid.
abstract: Eicosanoids are important mediators of fever, pain, and inflammation that modulate cell signaling during acute and chronic disease. We show by using lipidomics that thrombin-activated human platelets generate a new type of eicosanoid that both stimulates and primes human neutrophil integrin (Mac-1) expression, in response to formylmethionylleucylphenylalanine. Detailed characterization proposes a dioxolane structure, 8-hydroxy-9,11-dioxolane eicosatetraenoic acid (dioxolane A3, DXA3). The lipid is generated in nanogram amounts by platelets from endogenous arachidonate during physiological activation, with inhibition by aspirin in vitro or in vivo, implicating cyclooxygenase-1 (COX). Pharmacological and genetic studies on human/murine platelets revealed that DXA3 formation requires protease-activated receptors 1 and 4, cytosolic phospholipase A2 (cPLA2), Src tyrosine kinases, p38 MAPK, phospholipase C, and intracellular calcium. From data generated by purified COX isoforms and chemical oxidation, we propose that DXA3 is generated by release of an intermediate from the active site followed by oxygenation at C8. In summary, a new neutrophil-activating platelet-derived lipid generated by COX-1 is presented that can activate or prime human neutrophils, suggesting a role in innate immunity and acute inflammation.
authors.affiliation: From the Systems Immunity Research Institute and Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom.
authors.forename: Christine
authors.initials: C
authors.lastname: Hinz
authors.affiliation: From the Systems Immunity Research Institute and Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom.
authors.forename: Maceler
authors.initials: M
authors.lastname: Aldrovandi
authors.affiliation: the Department of Pharmacology, University of Colorado at Denver, Aurora, Colorado 80045.
authors.forename: Charis
authors.initials: C
authors.lastname: Uhlson
authors.affiliation: the Vanderbilt Institute of Chemical Biology, Centre in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee 37232-0146, and.
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Marnett
authors.affiliation: the William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom.
authors.forename: Hilary J
authors.initials: HJ
authors.lastname: Longhurst
authors.affiliation: the William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Warner
authors.affiliation: From the Systems Immunity Research Institute and Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom.
authors.forename: Saydul
authors.initials: S
authors.lastname: Alam
authors.affiliation: From the Systems Immunity Research Institute and Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom.
authors.forename: David A
authors.initials: DA
authors.lastname: Slatter
authors.affiliation: From the Systems Immunity Research Institute and Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom.
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Lauder
authors.affiliation: From the Systems Immunity Research Institute and Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom.
authors.forename: Keith
authors.initials: K
authors.lastname: Allen-Redpath
authors.affiliation: From the Systems Immunity Research Institute and Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Collins
authors.affiliation: the Department of Pharmacology, University of Colorado at Denver, Aurora, Colorado 80045.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Murphy
authors.affiliation: From the Systems Immunity Research Institute and Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Thomas
authors.affiliation: From the Systems Immunity Research Institute and Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom, O-DonnellVB@cardiff.ac.uk.
authors.forename: Valerie B
authors.initials: VB
authors.lastname: O'Donnell
mesh_terms: D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001792:Blood Platelets / Q000201:enzymology* / Q000276:immunology; D051545:Cyclooxygenase 1 / Q000276:immunology / Q000378:metabolism*; D004148:Dioxolanes / Q000276:immunology / Q000378:metabolism*; D007113:Immunity, Innate / Q000187:drug effects / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D016177:Macrophage-1 Antigen / Q000276:immunology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018375:Neutrophil Activation / Q000187:drug effects / Q000502:physiology*; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism*; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology
chemical_list: D004148:Dioxolanes; D016177:Macrophage-1 Antigen; D008565:Membrane Proteins; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; C496512:Ptgs1 protein, mouse; D001241:Aspirin; C010962:formal glycol
keywords: cyclooxygenase (COX); eicosanoid; eicosanoid biosynthesis; lipid; lipidomics; platelet