Am. J. Respir. Cell Mol. Biol., Volume 20, Number 1, January, 1999 163-170

5-oxo-6,8,11,14-Eicosatetraenoic Acid Is a Potent Stimulator of L-Selectin Shedding, Surface Expression of CD11b, Actin Polymerization, and Calcium Mobilization in Human Eosinophils

William S. Powell, Sylvie Gravel, and Fawaz Halwani

Departments of Medicine and Pathology, McGill University, Montreal, Quebec, Canada

5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is a metabolite of arachidonic acid formed by the oxidation of 5-hydroxy-6,8,11,14-eicosatetraenoic acid by a highly specific dehydrogenase. 5-oxo-ETE is a chemoattractant for both neutrophils and eosinophils. Although it is not as effective as leukotriene B₄ (LTB₄) and platelet-activating factor (PAF) in stimulating neutrophil migration, we found that it is considerably more active than these and a variety of other lipid mediators as an eosinophil chemoattractant. Moreover, low concentrations of 5-oxo-ETE appear to enhance the responsiveness of these cells to PAF. The objectives of the current investigation were to identify rapid responses induced in eosinophils by 5-oxo-ETE that might be related to the infiltration of these cells into tissues. We found that 5-oxo-ETE is more effective than PAF and LTB₄ in inducing both L-selectin shedding and actin polymerization in human eosinophils, whereas PAF is the most active of these mediators in stimulating calcium mobilization. The complementary effects of 5-oxo-ETE and PAF on actin polymerization and calcium mobilization may explain their synergistic effect on eosinophil migration. 5-oxo-ETE and PAF were equipotent in stimulating the surface expression of the ₂-integrin CD11b, but were slightly less potent than LTB₄. 5-oxo-ETE- induced actin polymerization was subject to homologous but not heterologous desensitization. It was not prevented by incubation of eosinophils with inhibitors of protein kinase C (staurosporine), mitogen-activated protein kinase kinase (PD98059), or phosphatidylinositol-3-kinase (wortmannin). In conclusion, 5-oxo-ETE is a potent activator of human eosinophils and may be an important regulator of tissue infiltration of these cells.

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