Eoxins Are Proinflammatory Arachidonic Acid Metabolites Produced via the 15-Lipoxygenase-1 Pathway in Human Eosinophils and Mast Cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 2; pp. 680 - 685
• Main Authors: Feltenmark, Stina, Gautam, Narinder, Brunnström, Åsa, Griffiths, William, Backman, Linda, Edenius, Charlotte, Lindbom, Lennart, Björkholm, Magnus, Claesson, Hans-Erik
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 15-01-2008; National Acad Sciences
• Subjects: Arachidonate 15-Lipoxygenase - metabolism; Arachidonic Acid - metabolism; Asthma; Biological Sciences; Calcium; Calcium - metabolism; Cells; Cellular metabolism; Chromatography, Liquid - methods; Enzymes; Eosinophils; Eosinophils - enzymology; Epithelial cells; Fatty acids; Gene Expression Regulation, Enzymologic; Histamines; Humans; Interleukin-6 - metabolism; Leukocytes; Leukotriene C4 - metabolism; Leukotriene C4 - physiology; Leukotriene E4 - analogs & derivatives; Leukotriene E4 - metabolism; Leukotriene E4 - pharmacology; Leukotriene E4 - physiology; Leukotrienes - chemistry; Leukotrienes - pharmacology; Mass Spectrometry - methods; Mast cells; Mast Cells - enzymology; Mast Cells - metabolism; Medicin och hälsovetenskap; Metabolites; Models, Biological; Models, Chemical; Nasal polyps; Prostaglandin D2 - metabolism; Proteins; Spectrometry, Mass, Electrospray Ionization - methods; Tissues
• DOI: 10.1073/pnas.0710127105
• EISSN: 1091-6490
• ISSN: 0027-8424; 1091-6490

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.