Induction of cyclooxygenase-2 and enhanced release of prostaglandin E(2) and I(2) in human endothelial cells by engagement of CD40.

ABSTRACT

OBJECTIVES: The hypothesis was tested that CD40-CD154 interaction is involved in the induction of cyclooxygenase-2 and the release of prostanoids in human endothelial cells. METHODS AND RESULTS: In a coculture model of human endothelial cells and a transfected CD154 positive cell line, engagement of CD40 on endothelial cells dramatically increased the synthesis of prostacyclin, prostaglandin E(2) and thromboxane A(2). This upregulation was mediated through an induction of cyclooxygenase-2 (Cox-2), as it was blocked by Cox-2-selective inhibitors. Western blot analysis demonstrated that Cox-2 protein was markedly increased in endothelial cells following CD40 engagement, an effect that was inhibited by pretreatment of cells with an anti-CD154 antibody. CONCLUSION: The data indicate that signaling via CD40 constitutes a major pathway in human endothelial cells for the induction of Cox-2 and release of prostanoids. The CD40-Cox-2 axis thus may represent an important pathway for initiating or maintaining an inflammatory process at the vessel wall.