title: Activation of lymphocyte function-associated molecule-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) mimicked by an antibody directed against CD18.
abstract: The beta 2-integrin (CD18) family members bind to their ligands subsequent to activation of a number of well defined and diverse signal transduction pathways. The precise molecular changes associated with activation of the integrin family members have remained elusive. Here, we characterize a monoclonal, CBR LFA-1/2, that binds to the beta 2-subunit and is able to mimic activation induced upon stimulation by phorbol esters. The Ab induces binding of the LFA-1-expressing cell line, JY, to ICAM-1 (CD54) and ICAM-3 (CD50). Activation of binding by this Ab is independent of Fc interactions and does not occur through cross-linking at the cell surface, because the Fab fragment of the Ab is able to modulate the same effect. Stimulation of neutrophils with CBR LFA-1/2 induces binding to ICAM-1 through activation of both LFA-1 and Mac-1. Activation of Mac-1 by CBR LFA-1/2 was further confirmed by stimulation of neutrophil binding to fibrinogen, a ligand for Mac-1. CBR LFA-1/2 lowers by 10-fold the concentration of Mg2+ required to achieve maximal binding of LFA-1 to ICAM-1. It therefore appears that CBR LFA-1/2 induces a conformational change that directly increases the avidity of beta 2-integrins for ligands.
authors.affiliation: Harvard Medical School, Center for Blood Research, Boston, MA 02115, USA.
authors.forename: L
authors.initials: L
authors.lastname: Petruzzelli
authors.forename: L
authors.initials: L
authors.lastname: Maduzia
authors.forename: T A
authors.initials: TA
authors.lastname: Springer
mesh_terms: D018033:Antibodies, Bispecific / Q000276:immunology* / Q000494:pharmacology; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018821:CD18 Antigens / Q000276:immunology*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002460:Cell Line; D005340:Fibrinogen / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology / Q000378:metabolism*; D016177:Macrophage-1 Antigen / Q000276:immunology / Q000378:metabolism*; D008274:Magnesium / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding / Q000502:physiology; D011961:Receptors, Fc / Q000378:metabolism
chemical_list: D018033:Antibodies, Bispecific; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018821:CD18 Antigens; D015815:Cell Adhesion Molecules; C483616:ICAM3 protein, human; D007140:Immunoglobulin Fab Fragments; D016169:Lymphocyte Function-Associated Antigen-1; D016177:Macrophage-1 Antigen; D011961:Receptors, Fc; D018799:Intercellular Adhesion Molecule-1; D005340:Fibrinogen; D008274:Magnesium