Cysteinyl leukotrienes induce human eosinophil locomotion and adhesion molecule expression via a CysLT1 receptor-mediated mechanism.

Abstract

The mechanisms involved in eosinophil recruitment by cysteinyl-leukotrienes (CysLTs) remain to be defined. We investigated whether CysLTs LTC4, LTD4 and LTE4 could directly stimulate in vitro adhesion molecule expression and cell locomotion of blood eosinophils from atopic asthmatic donors. Mab staining and FACS analysis were used to evaluate Mac-1 and LFA-1 expression on eosinophils before and after CysLTs stimulation. Eosinophil locomotion was tested using a 48-well Boyden microchamber. CysLTs, at the concentrations of 1 and 10 nM, were able to significantly up-regulate Mac-1 expression (P < 0.05, each comparison) but not LFA-1 expression (P > 0.05, each comparison). A dose-dependent, eosinophil chemotaxis was also induced by LTC4, LTD4 and LTE4 (0.1-10 nM) (P < 0.01, each comparison). Montelukast (0.01 nM to 10 nM), a specific CysLT1 receptor antagonist, significantly down-regulated LTC4, LTD4 and LTE4-induced Mac-1 expression (P < 0.01, each comparison) and the CysLT-induced eosinophil migration (P < 0.01, each comparison). In contrast, montelukast did not affect Mac-1 expression or cell migration when eosinophils were stimulated by the 'non-specific activators', such as fMLP or C5a (P > 0.05, each comparison). These data demonstrate that CysLTs are active in vitro in directly up-regulating human eosinophil functions involved in eosinophil recruitment. The down-regulation of Mac-1 expression and eosinophil chemotaxis by the potent and selective CysLT1 receptor antagonist montelukast indicated the specificity of the LTC4-, LTD4- and LTE4-induced response.