Cysteinyl leukotrienes induce P-selectin expression in human endothelial cells via a non-CysLT₁ receptor-mediated mechanism

Cysteinyl leukotrienes are bioactive lipid mediators known to possess potent proinflammatory actions included in these are effects on vascular endothelium to promote surface expression of the adhesion molecule P- selectin. In the present study we were interested in investigating the receptor mechanism(s) involved in cysteinyl leukotriene-induced endothelial P-selectin expression. As such we examined the effect of several potent and selective cysteinyl leukotriene receptor antagonists on this response. Incubation of cultured human umbilical vein endothelial cells (HUVEC) with the cysteinyl leukotrienes leukotriene C₄ (LTC₄) or leukotriene D₄ (LTD₄) induced surface expression of P-selectin which was concentration dependent and rapid in onset. Expression of endothelial P-selectin induced by either LTC₄ or LTD₄ was not blocked however by pretreatment of HUVEC with the selective cysteinyl leukotriene-1 (CysLT₁) receptor antagonists SKF 104353, pranlukast or zafirlukast before agonist exposure. In contrast, SKF 104353 effectively antagonized the LTC₄-induced contractions in isolated human bronchial smooth muscle preparations, shifting the agonist dose-response curve to the right by some 3 log-fold in this tissue. The present results suggest that cysteinyl leukotrienes induce surface expression of endothelial P-selectin via a mechanism independent of the CysLT₁ receptor.