Abstract
BackgroundDuring inflammation, adhesion molecules regulate recruitment of leukocytes to inflamed tissues. It is reported that vascular cell adhesion molecule-1 (VCAM-1) activates extracellular regulated kinases 1 and 2 (ERK1/2), but the mechanism for this activation is not known. Pharmacological inhibitors of ERK1/2 partially inhibit leukocyte transendothelial migration in a multi-receptor system but it is not known whether VCAM-1 activation of ERK1/2 is required for leukocyte transendothelial migration (TEM) on VCAM-1.Methodology/Principal FindingsIn this study, we identified a mechanism for VCAM-1 activation of ERK1/2 in human and mouse endothelial cells. VCAM-1 signaling, which occurs through endothelial cell NADPH oxidase, protein kinase Cα (PKCα), and protein tyrosine phosphatase 1B (PTP1B), activates endothelial cell ERK1/2. Inhibition of these signals blocked VCAM-1 activation of ERK1/2, indicating that ERK1/2 is activated downstream of PTP1B during VCAM-1 signaling. Furthermore, VCAM-1-specific leukocyte migration under physiological laminar flow of 2 dynes/cm2 was blocked by pretreatment of endothelial cells with dominant-negative ERK2 K52R or the MEK/ERK inhibitors, PD98059 and U0126, indicating for the first time that ERK regulates VCAM-1-dependent leukocyte transendothelial migration.Conclusions/SignificanceVCAM-1 activation of endothelial cell NADPH oxidase/PKCα/PTP1B induces transient ERK1/2 activation that is necessary for VCAM-1-dependent leukocyte TEM.
Highlights
The transendothelial migration (TEM) of leukocytes is critical for inflammatory responses, immune surveillance, leukocyte homing and mobilization of hematopoietic progenitor cells [1]
We determined whether endothelial MEK1/2 and ERK2 are required for VCAM-1dependent leukocyte migration
We report that vascular cell adhesion molecule-1 (VCAM-1) activation of extracellular regulated kinases 1 and 2 (ERK1/2) participates in VCAM-1-dependent leukocyte transendothelial migration and identify a mechanism for VCAM-1 activation of ERK1/2 in endothelial cells
Summary
The transendothelial migration (TEM) of leukocytes is critical for inflammatory responses, immune surveillance, leukocyte homing and mobilization of hematopoietic progenitor cells [1]. Leukocyte binding to vascular cell adhesion molecule-1 (VCAM-1) triggers signaling events in endothelial cells that are critical during VCAM-1-dependent TEM. VCAM-1 signals through ROS, PKCa, and PTP1B are required for VCAM-1-dependent leukocyte TEM in vitro [4,5,6,7,8]. It has been reported that NOX2 and ROS are required for VCAM-1-dependent leukocyte recruitment in vivo [4,9,10,11]. It is reported that vascular cell adhesion molecule-1 (VCAM-1) activates extracellular regulated kinases 1 and 2 (ERK1/2), but the mechanism for this activation is not known. Pharmacological inhibitors of ERK1/2 partially inhibit leukocyte transendothelial migration in a multi-receptor system but it is not known whether VCAM-1 activation of ERK1/2 is required for leukocyte transendothelial migration (TEM) on VCAM-1
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