Winter Michael C, Shasby Sandra S, Ries Dana R, Shasby D Michael
Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA.
Am J Physiol Lung Cell Mol Physiol. 2004 Oct;287(4):L816-23. doi: 10.1152/ajplung.00056.2004. Epub 2004 Jun 25.
Histamine is an important agent of innate immunity, transiently increasing the flux of immune-competent molecules from the vascular space to the tissues and then allowing rapid restoration of the integrity of the endothelial barrier. In previous work we found that histamine alters the endothelial barrier by disrupting cell-cell adhesion and identified VE-cadherin as an essential participant in this process. The previous work did not determine whether histamine directly interrupted VE-cadherin adhesion, whether the effects of histamine were selective for cadherin adhesion, or whether capacitive calcium flux across the cell membrane was necessary for the effects of histamine on cell-cell adhesion. In the current work we found that histamine directly interrupts adhesion of L cells expressing the type 1 histamine (H1) receptor and VE-cadherin to a VE-cadherin-Fc fusion protein. In contrast, integrin-mediated adhesion to fibronectin of the same L cells expressing the H1 receptor was not affected by histamine, demonstrating that the effects of histamine are selective for cadherin adhesion. Some of the effects of many edemagenic agonists on endothelium are dependent on the capacitive flux of calcium across the endothelial cell membrane. Blocking capacitive calcium flux with LaCl3 did not prevent histamine from interrupting VE-cadherin adhesion of transfected L cells, nor did it prevent histamine from interrupting cell-cell adhesion of human umbilical vein endothelial cells. These data support the contentions that histamine directly and selectively interrupts cadherin adhesion and this effect on cadherin adhesion is independent of capacitive calcium flux.
组胺是先天性免疫的重要介质，可短暂增加免疫活性分子从血管腔向组织的流量，然后使内皮屏障的完整性迅速恢复。在先前的研究中，我们发现组胺通过破坏细胞间黏附来改变内皮屏障，并确定血管内皮钙黏蛋白（VE-钙黏蛋白）是这一过程中的关键参与者。先前的研究并未确定组胺是否直接干扰VE-钙黏蛋白的黏附、组胺的作用是否对钙黏蛋白黏附具有选择性，或者细胞膜上的电容性钙内流对于组胺对细胞间黏附的作用是否必要。在当前的研究中，我们发现组胺直接干扰表达1型组胺（H1）受体和VE-钙黏蛋白的L细胞与VE-钙黏蛋白-Fc融合蛋白的黏附。相比之下，组胺对表达H1受体的相同L细胞整合素介导的与纤连蛋白的黏附没有影响，这表明组胺对钙黏蛋白黏附的作用具有选择性。许多致水肿激动剂对内皮的一些作用依赖于钙通过内皮细胞膜的电容性内流。用LaCl3阻断电容性钙内流并不能阻止组胺干扰转染L细胞的VE-钙黏蛋白黏附，也不能阻止组胺干扰人脐静脉内皮细胞的细胞间黏附。这些数据支持以下观点：组胺直接且选择性地干扰钙黏蛋白黏附，并且这种对钙黏蛋白黏附的作用与电容性钙内流无关。
