title: Adhesion molecule mechanisms mediating monocyte migration through synovial fibroblast and endothelium barriers: role for CD11/CD18, very late antigen-4 (CD49d/CD29), very late antigen-5 (CD49e/CD29), and vascular cell adhesion molecule-1 (CD106).
abstract: Monocytes migrate through vascular endothelium, and then in connective tissue. As a model of this process, we investigated adhesion molecules involved in monocyte migration through HUVEC and a barrier of human synovial fibroblasts (HSF). Minimal spontaneous monocyte migration (6-7%) occurred through either cell barrier, but this increased markedly (27-35% of added monocytes) when a C5a chemotactic gradient was present. Migration across unstimulated HUVEC was partially inhibited (40%) by mAb to CD18 (beta2 integrin) and completely blocked by anti-CD18 plus anti-alpha4 (CD49d; very late Ag-4 (VLA-4)) mAbs. In contrast, migration across HSF induced by C5a or monocyte chemoattractant protein-1 was not inhibited by mAb to CD18 and was only partially inhibited (33%) in combination with anti-alpha4 mAb. The CD18- and VLA-4-independent migration across HSF was completely inhibited by mAb to alpha5 of VLA-5. The inhibitory effect of mAbs to VLA-4 and VLA-5 was on the monocyte and required blockade of CD11/CD18 to be observed. In contrast to HSF, no role for VLA-5 in monocyte transendothelial migration was detected. Both HSF and IL-1-stimulated HUVEC expressed vascular cell adhesion molecule-1 (VCAM-1). However, VLA-4-mediated monocyte migration across HSF was only partially dependent on VCAM-1, in contrast to transendothelial migration, which was completely blocked by anti-VCAM-1 mAbs. In conclusion, unlike transendothelial migration, for which VLA-4 is the alternative mechanism to CD11/CD18 on monocytes, both VLA-4 and VLA-5 can mediate monocyte migration through fibroblast barriers. In addition to VCAM-1, other ligand(s) on HSF are also involved in the VLA-4-mediated migration.
authors.affiliation: Department of Pediatrics, Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: X Z
authors.initials: XZ
authors.lastname: Shang
authors.forename: B J
authors.initials: BJ
authors.lastname: Lang
authors.forename: A C
authors.initials: AC
authors.lastname: Issekutz
mesh_terms: D000911:Antibodies, Monoclonal; D018845:CD11 Antigens / Q000502:physiology*; D018821:CD18 Antigens / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000502:physiology*; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000494:pharmacology; D015936:Complement C5a / Q000502:physiology; D004727:Endothelium / Q000166:cytology*; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D007158:Immunologic Techniques; D039041:Integrin alpha4beta1; D039121:Integrin alpha6beta1; D016023:Integrins / Q000502:physiology*; D009000:Monocytes / Q000166:cytology*; D017469:Receptors, Fibronectin / Q000502:physiology*; D016201:Receptors, Lymphocyte Homing / Q000502:physiology*; D013583:Synovial Membrane / Q000166:cytology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; D018845:CD11 Antigens; D018821:CD18 Antigens; D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2; D039041:Integrin alpha4beta1; D039121:Integrin alpha6beta1; D016023:Integrins; D017469:Receptors, Fibronectin; D016201:Receptors, Lymphocyte Homing; D019010:Vascular Cell Adhesion Molecule-1; D015936:Complement C5a