5-Oxo-6,8,11,14-eicosatetraenoic acid is a potent stimulator of human eosinophil migration

Abstract

Human neutrophils and monocytes contain a highly specific dehydrogenase 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 levels and migration and have now investigated its effects on human eosinophils. 5-Oxo-ETE is a potent stimulus of eosinophil migration, with significant effects being detected at concentrations as low as 1 nM and a maximal response at 1 microM. The responses elicited by 5-oxo-ETE were about two to three times greater than those to platelet-activating factor (PAF) and 5-oxo-15-hydroxy-6,8,11,13-eicosatetraenoic acid (5-oxo-15-hydroxy-ETE) at all concentrations tested between 10 nM and 1 microM. Leukotrienes B4 and D4 also significantly stimulated eosinophil migration, 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-ETE (1 nM) potentiated eosinophil migration in response to PAF. Eosinophils 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 C4, cysteine-containing lipoxins, and 5,15-dihydroxy-6E,8Z,11Z,13E-eicosatetraenoic acid. In summary, of all the lipid mediators tested, 5-oxo-ETE was the most effective in stimulating migration of human eosinophils. Although eosinophils are capable of synthesizing 5-oxo-eicosanoids, the amounts detected were relatively small, and other leukocytes such as neutrophils, monocytes, or macrophages may be more important sites for the synthesis of this compound.