Occupancy of CD11b/CD18 (Mac-1) divalent ion binding site(s) induces leukocyte adhesion.
The group of leukocyte integrins CD11a-c/CD18 coordinate disparate adhesion reactions in the immune system through a regulated process of ligand recognition. The participation of the receptor divalent ion binding site(s) in this mechanism of ligand binding has been investigated. As compared with other divalent cations, Mn2+ ions have the unique property to dramatically stimulate the adhesive functions of the leukocyte integrin CD11b/CD18 (Mac-1), expressed on myelo-monocytic cells. This is reflected in a three- to fivefold increased early monocyte adhesion (less than 20 min) to resting, unperturbed endothelial cells, and increased association of CD11b/CD18 with its soluble ligands fibrinogen and factor X. CD11b/CD18 ligand recognition in the presence of Mn2+ ions is specific, time and concentration dependent, and inhibited by anti-CD11b mAb. At variance with Ca(2+)-containing reactions where CD11b/CD18 functions as an inducible receptor activated by adenine nucleotides or chemoattractants, Mn2+ ions induce per se a constitutive maximal ligand binding capacity of CD11b/CD18, that is not further modulated by cell stimulation. Rather than quantitative changes in surface density, Mn2+ ions increase the affinity of CD11b/CD18 for its complementary ligands up to 10-fold, as judged by Scatchard plot analysis of receptor:ligand interaction under these conditions. Furthermore, monocyte exposure to Mn2+ ions induces the expression of activation-dependent neo-antigenic epitopes on CD11b/CD18, selectively recognized by mAb 7E3. These data suggest that in addition to cell-activating stimuli, favorable engagement of divalent ion binding site(s) can provide an alternative pathway to rapidly regulate the receptor affinity of leukocyte integrins.
Altieri
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Department of Immunology, Research Institute of Scripps Clinic, La Jolla, CA 92037.
D002413:Cations, Divalent; D002448:Cell Adhesion; D002460:Cell Line; D004730:Endothelium, Vascular / Q000166:cytology; D005170:Factor X / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D016177:Macrophage-1 Antigen / Q000502:physiology*; D008345:Manganese / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology
D002413:Cations, Divalent; D008024:Ligands; D016177:Macrophage-1 Antigen; D008345:Manganese; D009240:N-Formylmethionine Leucyl-Phenylalanine; D005170:Factor X; D005340:Fibrinogen