ACTIVATION OF POLYMORPHONUCLEAR LEUKOCYTES REDUCES THEIR ADHESION TO P-SELECTIN AND CAUSES REDISTRIBUTION OF LIGANDS FOR P-SELECTIN ON THEIR SURFACES
ACTIVATION OF POLYMORPHONUCLEAR LEUKOCYTES REDUCES THEIR ADHESION TO P-SELECTIN AND CAUSES REDISTRIBUTION OF LIGANDS FOR P-SELECTIN ON THEIR SURFACES
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DOI：
10.1172/jci118018
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发表时间：
1995-07-01
影响因子：
15.9
通讯作者：
ZIMMERMAN, GA
中科院分区：
文献类型：
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作者：
LORANT, DE;MCEVER, RP;ZIMMERMAN, GA
在急性炎症反应中，选择素介导中性粒细胞(PMN)沿内皮细胞表面的初始滚动。紧随其后的是紧密的黏附，这需要依赖于激活上调PMN上的CD11/CD18整合素。为了发生迁移，在内皮细胞表面建立的初始结合必须被解除。我们发现，PMN的激活导致它们脱离P-选择素，P-选择素是一种表达在炎症内皮表面的糖蛋白，介导了PMN的初始拴系。当中性粒细胞被与P-选择素共表达的血小板激活因子或其他信号分子激活时，就会发生键的松动。与CD11/CD18整合素的上调相比，P-选择素的粘附性降低的时间进程表明，当激活的PMN在体内迁移时，可能会发生“债券交易”。中性粒细胞的激活并没有改变P-选择素与液体相的结合，表明P-选择素的配体(S)没有脱落或内化。使用包裹了P-选择素的微球，我们发现P-选择素的配体随机分布在圆形的、未激活的PMN的表面。抗P-选择素糖蛋白配体-1(PSGL-1)的抗体完全抑制P-选择素糖蛋白配体-1的结合，提示P-选择素糖蛋白配体-1是本实验中的关键结合部位，与未激活的PMN上的分散模式相反，P-选择素的配体定位于激活的极化细胞的尾足上。活化前用细胞松弛素D处理PMN可阻止P-选择素包裹的微球的细胞形状改变、结合部位的重新分布以及细胞对P-选择素的粘附性的降低。这些实验表明，P-选择素的配体分布受到细胞激活和细胞骨架相互作用的影响，而这些配体的重新分布可能会影响粘附性相互作用。中性粒细胞的激活可能导致P-选择素及其配体之间的键松动或解离，从而促进跨内皮细胞的迁移。
In acute inflammatory responses, selectins mediate initial rolling of neutrophils (PMNs) along the endothelial surface. This is followed by tight adhesion that requires activation-dependent up-regulation of CD11/CD18 integrins on PMNs. For emigration to occur, the initial bonds that are established at the endothelial surface must be disengaged. We show that activation of PMNs results in their detachment from P-selectin, a glycoprotein expressed at the surface of inflamed endothelium that mediates initial tethering of PMNs. Loosening of the bond occurs when PMNs are activated by platelet-activating factor, which is coexpressed with P-selectin, or by other signaling molecules. The time course of reduced adhesion to P-selectin, when compared to up-regulation of CD11/CD18 integrins, suggests that ''bond trading'' may occur as activated PMNs transmigrate in vivo. Activation of PMNs did not alter binding of fluid-phase P-selectin, indicating that the ligand(s) for P-selectin is not shed or internalized. Using microspheres coated with P-selectin, we found that ligands for P-selectin were randomly distributed over the surfaces of rounded, unactivated PMNs. An antibody against P-selectin glycoprotein ligand-1 (PSGL-1) completely inhibited binding of P-selectin-coated beads suggesting that P-selectin glycoprotein ligand-1 is the critical binding site in this assay, In contrast to the dispersed pattern on unactivated PMNs, the ligands for P-selectin were localized on the uropods of activated, polarized cells. Pretreating PMNs with cytochalasin D before activation prevented the change in cell shape, the redistribution of binding sites for P-selectin-coated beads, and the decrease in cellular adhesiveness for P-selectin. These experiments indicate that the distribution of ligands for P-selectin is influenced by cellular activation and by cytoskeletal interactions, and that redistribution of these ligands may influence adhesive interactions. Activation of PMNs may cause loosening or disengagement of bonds between P-selectin and its ligands, facilitating transendothelial migration.