title: 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 alpha4 peptide. Low concentrations (5-10 microM) 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 (> or = 100 microM) of hydrogen peroxide inhibited the binding. Exogenous hydrogen peroxide and glutathione induced molecular modification of S-glutathionylation on the alpha4 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.
authors.affiliation: National Cheng Kung University Medical College, Graduate Institute of Basic Medicine, Tainan, Taiwan.
authors.forename: Si-Yen
authors.initials: SY
authors.lastname: Liu
authors.forename: Min-Yi
authors.initials: MY
authors.lastname: Tsai
authors.forename: Kuo-Pin
authors.initials: KP
authors.lastname: Chuang
authors.forename: Ya-Fang
authors.initials: YF
authors.lastname: Huang
authors.forename: Chi-Chang
authors.initials: CC
authors.lastname: Shieh
mesh_terms: D002448:Cell Adhesion; D002999:Clone Cells; D018922:HL-60 Cells; D006801:Humans; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008024:Ligands; D010084:Oxidation-Reduction; D011485:Protein Binding; D011487:Protein Conformation; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D039041:Integrin alpha4beta1; D008024:Ligands; D021122:Protein Subunits; D013438:Sulfhydryl Compounds; D019010:Vascular Cell Adhesion Molecule-1