Eoxins are proinflammatory arachidonic acid metabolites produced via the 15-lipoxygenase-1 pathway in human eosinophils and mast cells

摘要

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)C_4 in reverse-phase HPLC. Analysis with positive-ion electrospray tandem MS identified this eosinophil metabolite as 14,15-LTC_4. This metabolite could be metabolized to 14,15-LTD_4 and 14,15-LTE_4 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)C_4, -D_4, and -E_4 instead of 14,15-LTC_4, -D_4, and -E_4, respectively. Cord blood-derived mast cells and surgically removed nasal polyps from allergic subjects also produced EXC_4. Incubation of eosinophils with arachidonic acid favored the production of EXC_4, whereas challenge with calcium ionophore led to exclusive formation of LTC_4. Eosinophils produced EXC_4 after challenge with the proinflammatory agents LTC_4, prostaglandin D_2, and IL-5, demonstrating that EXC_4 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 LTC_4 and LTD_4. Taken together, this article describes the formation of proinflammatory EXs, in particular in human eosinophils but also in human mast cells and nasal polyps.