Ligand binding of leukocyte integrin very late antigen-4 involves exposure of sulfhydryl groups and is subject to redox modulation

Abstract

Activation of leukocyte integrins is important for selective recruitment of cells from the circulation to tissues. Our previous studies showed that the binding between the integrin very late antigen-4 (VLA-4) and vascular cell adhesion molecule-1 (VCAM-1) is modulated by reactive oxygen species. In this study, we investigated the molecular nature of redox modulation on the activation states of VLA-4 on. human leukocytes. We found that ligand binding of VLA-4 induced exposure of sulfhydryl groups on the α4 peptide. Low concentrations (5-10 μM) of exogenous hydrogen peroxide in the presence or absence of added glutathione enhanced the ligand binding ability of VLA-4 to VCAM-1. and cell rolling on VCAM-1, while higher concentrations (≥100 μM) of hydrogen peroxide inhibited the binding. Exogenous hydrogen peroxide and glutathione induced molecular modification of S-glutathionylation on the α4 peptide. The redox regulation of the VLA-4 binding activity required outside-in signaling and cytoskeleton rearrangement. Our results indicate that ligand binding of VLA-4 involves redox modulations which may play a pivotal role in regulating the activation states of VLA-4 in inflammatory tissues and hence direct leukocyte trafficking. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.