VCAM-1 signaling in endothelial cells for lymphocyte migration.

摘要

Leukocyte migration is important for (patho-) physiological processes. The role of the leukocyte during migration has been well characterized; however, the function of the endothelium during lymphocyte migration is relatively unknown. Adhesion molecules on the endothelial cells are known to play a role in leukocyte rolling and capture. Recently, it has been demonstrated that these adhesion molecules mediate endothelial cell signals upon leukocyte binding. Our laboratory has shown that lymphocyte binding to vascular cell adhesion molecule-1 (VCAM-1) stimulates the activation of NADPH oxidase for the catalysis of low levels of reactive oxygen species (ROS). Activation of this enzyme complex is required for lymphocyte migration. This thesis describes a functional role for the VCAM-1-stimulated release of ROS in mediating actin structural changes within the endothelial cell necessary for lymphocyte migration. Furthermore, we have shown a mechanism for how these ROS modulate endothelial cell shape changes. VCAM-1-dependent release of ROS rapidly activates within minutes endothelial cell MMP-2 and MMP-9. Even though we demonstrate that VCAM-1-dependent ROS can activate lymphocyte MMP-9 hours after lymphocyte binding, it is the endothelial cell MMPs that are required for lymphocyte migration. This is the first report to examine endothelial cell MMP activity during lymphocyte migration. We further demonstrate that VCAM-1-dependent ROS can modulate endothelial cell shape changes through indirect activation of PTP1B. Activation of PTP1B is required for lymphocyte migration likely through modulation of endothelial cell junction proteins. In fact, we demonstrate that VCAM-1-dependent PTP1B activity causes increased serine phosphorylation of the tight junction protein zonula occludens-1 (ZO-1). Increased serine phosphorylation of ZO-1 increases epithelial cell permeability. This is the first report to determine a mechanism for how adhesion molecule signaling modulates endothelial cell junctions for lymphocyte migration. Taken together, these data further advance our knowledge of VCAM-1-mediated endothelial cell function during migration. It is important to understand VCAM-1 signaling for potential intervention of diseases such as atherosclerosis and tumor metastasis.