title: Eoxins are proinflammatory arachidonic acid metabolites produced via the 15-lipoxygenase-1 pathway in human eosinophils and mast cells.
abstract: Human eosinophils contain abundant amounts of 15-lipoxygenase (LO)-1. The biological role of 15-LO-1 in humans, however, is unclear. Incubation of eosinophils with arachidonic acid led to formation of a product with a UV absorbance maximum at 282 nm and shorter retention time than leukotriene (LT)C4 in reverse-phase HPLC. Analysis with positive-ion electrospray tandem MS identified this eosinophil metabolite as 14,15-LTC4. This metabolite could be metabolized to 14,15-LTD4 and 14,15-LTE4 in eosinophils. Because eosinophils are such an abundant source of these metabolites and to avoid confusion with 5-LO-derived LTs, we suggest the names eoxin (EX)C4, -D4, and -E4 instead of 14,15-LTC4, -D4, and -E4, respectively. Cord blood-derived mast cells and surgically removed nasal polyps from allergic subjects also produced EXC4. Incubation of eosinophils with arachidonic acid favored the production of EXC4, whereas challenge with calcium ionophore led to exclusive formation of LTC4. Eosinophils produced EXC4 after challenge with the proinflammatory agents LTC4, prostaglandin D2, and IL-5, demonstrating that EXC4 can be synthesized from the endogenous pool of arachidonic acid. EXs induced increased permeability of endothelial cell monolayer in vitro, indicating that EXs can modulate and enhance vascular permeability, a hallmark of inflammation. In this model system, EXs were 100 times more potent than histamine and almost as potent as LTC4 and LTD4. Taken together, this article describes the formation of proinflammatory EXs, in particular in human eosinophils but also in human mast cells and nasal polyps.
authors.affiliation: Biolipox AB, Berzelius Väg 3, SE-171 65 Solna, Sweden.
authors.forename: Stina
authors.initials: S
authors.lastname: Feltenmark
authors.forename: Narinder
authors.initials: N
authors.lastname: Gautam
authors.forename: Asa
authors.initials: A
authors.lastname: Brunnström
authors.forename: William
authors.initials: W
authors.lastname: Griffiths
authors.forename: Linda
authors.initials: L
authors.lastname: Backman
authors.forename: Charlotte
authors.initials: C
authors.lastname: Edenius
authors.forename: Lennart
authors.initials: L
authors.lastname: Lindbom
authors.forename: Magnus
authors.initials: M
authors.lastname: Björkholm
authors.forename: Hans-Erik
authors.initials: HE
authors.lastname: Claesson
mesh_terms: D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002853:Chromatography, Liquid / Q000379:methods; D004804:Eosinophils / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D017997:Leukotriene C4 / Q000378:metabolism / Q000502:physiology*; D017999:Leukotriene E4 / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D015289:Leukotrienes / Q000737:chemistry / Q000494:pharmacology; D013058:Mass Spectrometry / Q000379:methods; D008407:Mast Cells / Q000201:enzymology* / Q000378:metabolism; D008954:Models, Biological; D008956:Models, Chemical; D015230:Prostaglandin D2 / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods
chemical_list: C531124:14-cysteinyl-15-hydroxy-5,8,10,12-eicosatetraenoic acid; D015850:Interleukin-6; D015289:Leukotrienes; C526311:eoxin C4; D016718:Arachidonic Acid; D017997:Leukotriene C4; D017999:Leukotriene E4; D001093:Arachidonate 15-Lipoxygenase; D015230:Prostaglandin D2; D002118:Calcium