Eotaxin and RANTES enhance 5-oxo-6,8,11,14-eicosatetraenoic acid-induced eosinophil chemotaxis

Background: The 5-lipoxygenase product 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is a potent activator of human eosinophils and, among lipid mediators, is the most active chemoattractant for these cells. Studies have demonstrated the importance of 5-lipoxygenase products in allergen-induced pulmonary eosinophilia. Because CC chemokines such as eotaxin and RANTES also play critical roles in this phenomenon, it would seem likely that members of both classes of mediators contribute to this response. Objective: The study was designed to directly compare the effects of 5-oxo-ETE on eosinophils with those of eotaxin and RANTES and to determine whether these chemokines could enhance the chemotactic response to 5-oxo-ETE, Methods: Eosinophil chemotaxis was measured with microchemotaxis chambers. CD11b, L-selectin, and actin polymerization were measured by flow cytometry, Calcium mobilization was measured by fluorescence. Results: 5-Oxo-ETE stimulated eosinophil chemotaxis with a potency between those of eotaxin and RANTES and a maximal response about 50% higher than that of eotaxin, Threshold concentrations of eotaxin and RANTES increased the chemotactic potency of 5-oxo-ETE by more than 4-fold. 5-Oxo-ETE and eotaxin were approximately equipotent in mobilizing cytosolic calcium in eosinophils, Eotaxin was more potent in inducing CD11b expression and actin polymerization, but the maximal responses to 5-oxo-ETE were about 50% higher. 5-Oxo-ETE strongly induced L-selectin shedding, whereas eotaxin elicited only a weak and variable response, Conclusion: 5-Oxo-ETE is a strong activator of human eosinophils with a chemotactic potency comparable to those of eotaxin and RANTES, both of which enhance 5-oxo-ETE-induced chemotaxis. 5-Oxo-ETE and CC chemokines may combine to induce pulmonary eosinophilia in asthma.