5-OXO-6,8,11,14-EICOSATETRAENOIC ACID IS A POTENT STIMULATOR OF HUMANEOSINOPHIL MIGRATION

Human neutrophils and monocytes contain a highly specific dehydrogenas e which converts 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) to 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE). We have previously shown that 5-oxo-ETE is a potent stimulus of neutrophil calcium level s and migration and have now investigated its effects on human eosinop hils. 5-Oxo-ETE is a potent stimulus of eosinophil migration, with sig nificant effects being detected at concentrations as low as 1 nM and a maximal response at 1 mu M. The responses elicited by 5-oxo-ETE were about two to three times greater than those to platelet-activating fac tor (PAF) and 5-oxo-15-hydroxy-6,8,11,1 3-eicosatetraenoic acid (5-oxo -15-hydroxy-ETE) at all concentrations tested between 10 nM and 1 mu M . Leukotrienes B-4 and D-4 also significantly stimulated eosinophil mi gration, but the maximal responses to these agonists were only about 4 % of the maximal response to 5-oxo-ETE. A low concentration of 5-oxo-E TE (1 nM) potentiated eosinophil migration in response to PAF. Eosinop hils were capable of converting 5-HETE to 5-oxo-ETE, and this reaction was enhanced by phorbol myristate acetate. Stimulation of eosinophils with A23187 in the presence of low concentrations of arachidonic acid and phorbol 12-myristate 13-acetate led to the formation of 5-oxo-ETE and 5-oxo-15-hydroxy-ETE, but the amounts were considerably less than those of other eicosanoids such as leukotriene C-4, cysteine-containi ng lipoxins, and 5,15-dihydroxy-6E,8Z,11Z,13E-eicosatetraenoic acid. I n summary, of all the lipid mediators tested, 5-oxo-ETE was the most e ffective in stimulating migration of human eosinophils. Although eosin ophils are capable of synthesizing 5-oxo-eicosanoids, the amounts dete cted were relatively small, and other leukocytes such as neutrophils, monocytes, or macrophages may be more important sites for the synthesi s of this compound.