title: Differential regulation of beta 1 and beta 2 integrin avidity by chemoattractants in eosinophils.
abstract: The CC chemokines regulated on activation normal T expressed and secreted (RANTES) and monocyte chemotactic protein 3 (MCP-3), and the anaphylatoxin C5a, induce activation, degranulation, chemotaxis, and transendothelial migration of eosinophils. Adhesion assays on purified ligands showed differential regulation of beta 1 and beta 2 integrin avidity in eosinophils. Adhesiveness of VLA-4 (alpha 4 beta 1, CD29/CD49d) for vascular cell adhesion molecule 1 or fibronectin was rapidly increased but subsequently reduced by RANTES, MCP-3, or C5a. The deactivation of VLA-4 lead to cell detachment, whereas phorbol 12-myristate 13-acetate induced sustained activation of VLA-4. In contrast, chemoattractants stimulated a prolonged increase in the adhesiveness of Mac-1 (alpha M beta 2, CD11b/CD18) for intercellular adhesion molecule 1. Inhibition by pertussis toxin confirmed signaling via G protein-coupled receptors. Chemoattractants induced transient, while phorbol 12-myristate 13-acetate induced sustained actin polymerization. Disruption of actin filaments by cytochalasins inhibited increases in avidity of VLA-4 but not of Mac-1. Chemoattractants did not upregulate a Mn2+-inducible beta 1 neoepitope defined by the mAb 9EG7, but induced prolonged expression of a Mac-1 activation epitope recognized by the mAb CBRM1/5. This mAb inhibited chemoattractant-stimulated adhesion of eosinophils to intercellular adhesion molecule 1. Thus, regulation of VLA-4 was dependent on the actin cytoskeleton, whereas conformational changes appeared to be crucial for activation of Mac-1. To our knowledge, this is the first demonstration that physiological agonists, such as chemoattractants, can differentially regulate the avidity of a beta 1 and a beta 2 integrin expressed on the same leukocyte.
authors.affiliation: Center for Blood Research, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: C
authors.initials: C
authors.lastname: Weber
authors.forename: J
authors.initials: J
authors.lastname: Kitayama
authors.forename: T A
authors.initials: TA
authors.lastname: Springer
mesh_terms: D018821:CD18 Antigens / Q000502:physiology*; D002448:Cell Adhesion; D018946:Chemokine CCL5 / Q000378:metabolism; D054410:Chemokine CCL7; D002630:Chemotactic Factors / Q000502:physiology*; D002634:Chemotaxis, Leukocyte; D015936:Complement C5a / Q000378:metabolism; D016207:Cytokines; D004804:Eosinophils / Q000502:physiology*; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D039041:Integrin alpha4beta1; D019012:Integrin beta1 / Q000502:physiology*; D016023:Integrins / Q000502:physiology; D008024:Ligands; D016177:Macrophage-1 Antigen / Q000502:physiology; D018945:Monocyte Chemoattractant Proteins / Q000378:metabolism; D016201:Receptors, Lymphocyte Homing / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: C515450:CCL7 protein, human; D018821:CD18 Antigens; D018946:Chemokine CCL5; D054410:Chemokine CCL7; D002630:Chemotactic Factors; D016207:Cytokines; D005353:Fibronectins; D039041:Integrin alpha4beta1; D019012:Integrin beta1; D016023:Integrins; D008024:Ligands; D016177:Macrophage-1 Antigen; D018945:Monocyte Chemoattractant Proteins; D016201:Receptors, Lymphocyte Homing; D019010:Vascular Cell Adhesion Molecule-1; D015936:Complement C5a