Necessity of Thromboxane A_2 for Intiation of Platelet-Mediated Contact Sensitivity: Dual Activation of Platelets and Vascular Endothelial Cells

摘要

To investigate the crucial role of platelet-derived thromboxane A2 (TXA2) in initiating Ag-specific contact sensitivity (CS), a platelet-dependent CS model using geneticaUy mast ceU-deficient W/WV mice, was provided. In vivo treatment with BA Yu340S, a TXA2 receptor antagonist, markedly suppressed CS responses in a dose-dependent manner. This inhibitory effect occurred when HA Yu340S was administered before an early initiating phase, suggesting that TXA2 may be a potent initiator of platelet-mediated CS responses. When platelets were pretreated with BA Yu340S in vitro, platelet aggregation as weU as serotonin release, which is able to induce the early phase response aUowing local recruitment of CS effector T ceUs due to direct activation of vascular endothelial ceUs, was inhibited. The addition of U46619, a TXA2 agonist, or a mixture of platelets and thrombin-enhanced expression of both ICAM-1 and VCAM-1 on isolated mouse aortic endothelial cells, which was completely abolished by pretreat- ment with BA Yu340S. Furthermore, intradermal injection of U46619 into the ear of platelet-depleted mice led to CS responses with marked expression of ICAM-1 and VCAM-1 on the vascular endothelium. These findings suggest that TXA2 generated from platelets activated with Ag may mediate initiation of CS responses through inducing serotonin release from platelets and the subsequent aggregation and up-regulated expression of ICAM-1 and VCAM.1 on vascular endothelial ceUs.