CHEMICAL AND BIOLOGICAL CHARACTERIZATION OF OXO-EICOSATETRAENOIC ACIDS

Eicosatetraenoates (ETEs) with 5-oxo residues are known to induce huma n neutrophil (PMN) Ca2+ transients and chemotaxis. We find that 5-oxoE TE, 5-oxo-8-trans-ETE, 5 oxo-15-hydroxy-ETE, 5-hydroxy-ETE, 5-hydroxy- 15-oxoETE, 5,15-dioxoETE, and 5,15-dihydroxy-ETE have respective relat ive potencies of 10, 5, 3, 1, 0.2, 0.1, and 0.02 in: a) causing PMN to mobilize Ca2+, aggregate, and release small amounts of granule enzyme s and b) promoting large degranulation and oxidative burst responses i n PMN co-challenged with platelet-activating factor, tumor necrosis fa ctor-alpha, or ATP. Contrastingly, 12(R)-hydroxy-ETE, 12(S)-hydroxy-ET E, and 12-oxoETE induced PMN Ca2+ transients and aggregation [respecti ve potencies (5-hydroxy-ETE = 1) of 0.1, 0.01, and 0.003] but did not effect degranulation, and 15-hydroxy-ETE, 15-oxoETE, and 15-oxo-11-tra ns-ETE were inactive in all assays. Finally, 5-oxo/hydroxy-ETEs desens itized PMN to themselves but not to 12-oxo/hydroxy-ETEs or leukotriene (LT)B-4; 12-oxo/hydroxy-ETEs and LTB(4) desensitized PMN to themselve s and each other but not to 5-oxo/hydroxy-ETEs; 15-oxo/hydroxy-ETEs di d not desensitize PMN; and a LTB(4) receptor antagonist blocked respon ses to LTB(4) and 12-oxo/hydroxy-ETEs but not to 5-oxo/hydroxy-ETEs. T hus, 5-oxo/hydroxy-ETEs act by a common, LTB(4) receptor-independent m echanism that recognizes 5- but not 12- or 15-oxo/hydroxy-ETEs and pre fers oxo over hydroxy residues at C-5 whereas 12-oxo/hydroxy-ETEs act via a LTB(4) receptor mechanism that recognizes 12- but not 5- or 15-o xo/hydroxy-ETEs and prefers hydroxy over oxo residues at C-12.