title: Regulation of alpha 4 integrin-mediated adhesion of human eosinophils to fibronectin and vascular cell adhesion molecule-1.
abstract: BACKGROUND
  Eosinophils selectively accumulate at sites of allergic inflammation. Their recruitment is dependent on both the expression and functional activity of cell adhesion molecules. How the functional activity of cell adhesion molecules on eosinophils is regulated is poorly understood.
  
  
  OBJECTIVE
  Our objective was to examine the functional activity of alpha 4 integrins on human eosinophils and its regulation by various agents.
  
  
  METHODS
  Function of alpha 4 integrins on human eosinophils was examined by testing adhesion to immobilized fibronection and vascular cell adhesion molecule-1 (VCAM-1) in the presence or absence of a monoclonal antibody (mAb) (8A2) that activates beta 1 integrin function.
  
  
  RESULTS
  Spontaneous eosinophil adhesion to VCAM-1 was enhanced by 8A2, but adhesion to fibronectin could only be detected in the presence of 8A2. Concentrations of 8A2 that were approximately 100-fold less than saturating induced maximal eosinophil adhesion. Adhesion to VCAM-1 in the presence of 8A2 was effectively inhibited by alpha 4 and beta 1 integrin mAbs: beta 7 mAb had partial inhibitory activity. Connecting segment-1 peptide and alpha 4 mAb blocked 8A2-dependent fibronectin binding: beta 1, beta 2, and beta 7 integrin mAbs had partial inhibitory activity. Eosinophils obtained from bronchoalveolar lavage fluids and blood eosinophils stimulated with IL-5, platelet-activating factor, or RANTES displayed increased beta 2 integrin-dependent, not alpha 4 integrin-dependent, attachment. Spontaneous adhesion of eosinophils to VCAM-1 was significantly reduced by the tyrosine kinase inhibitor tyrphostin B46 (inhibitory concentration of 50% approximately equal to 20 mumol/L); this effect was reversed by 8A2.
  
  
  CONCLUSIONS
  The functional activity of integrins on eosinophils can be positively and negatively regulated. Altered integrin avidity may influence eosinophil recruitment in vivo.
authors.affiliation: Johns Hopkins Asthma and Allergy Center, Baltimore, MD 21224-6801, USA.
authors.forename: K
authors.initials: K
authors.lastname: Matsumoto
authors.forename: S A
authors.initials: SA
authors.lastname: Sterbinsky
authors.forename: C A
authors.initials: CA
authors.lastname: Bickel
authors.forename: D F
authors.initials: DF
authors.lastname: Zhou
authors.forename: N L
authors.initials: NL
authors.lastname: Kovach
authors.forename: B S
authors.initials: BS
authors.lastname: Bochner
mesh_terms: D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D001597:Benzylidene Compounds / Q000494:pharmacology; D002448:Cell Adhesion; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004804:Eosinophils / Q000502:physiology*; D005353:Fibronectins / Q000378:metabolism*; D006801:Humans; D039441:Integrin alpha4; D019012:Integrin beta1 / Q000276:immunology / Q000378:metabolism; D016023:Integrins / Q000276:immunology / Q000378:metabolism*; D019169:Jurkat Cells / Q000502:physiology; D007700:Kinetics; D009570:Nitriles / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D020032:Tyrphostins; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D001597:Benzylidene Compounds; D004791:Enzyme Inhibitors; D005353:Fibronectins; D019012:Integrin beta1; D016023:Integrins; D009570:Nitriles; D010446:Peptide Fragments; D020032:Tyrphostins; D019010:Vascular Cell Adhesion Molecule-1; C095713:alpha-cyano-(3,4-dihydroxy)-N-(3-phenylpropyl)cinnamide; D039441:Integrin alpha4; D011505:Protein-Tyrosine Kinases