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)/

Monocytes migrate through vascular endothelium, and then in connective tissue. As a model of this process, we investigated adhesion molecule s 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 presen t, Migration across unstimulated HUVEC was partially inhibited (40%) b y mAb to CD18 (beta(2) integrin) and completely blocked by anti-CD18 p lus anti-alpha(4) (CD49d; very late Ag-4 (VLA-4)) mAbs. In contrast, m igration 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-alpha(4) mAb. The CD18- and VLA-4-indepe ndent migration across HSF was completely inhibited by mAb to alpha(5) of VLA-5. The inhibitory effect of mAbs to VLA-4 and VLA-5 was on the monocyte and required blockade oi CD11/CD18 to be observed. In contra st to HSF, no role for VLA-5 in monocyte transendothelial migration wa s detected, Both HSF and IL-1-stimulated HUVEC expressed vascular cell adhesion molecule-1 (VCAM-1). However, VLA-4-mediated monocyte migrat ion 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 VL A-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 th e VLA-4-mediated migration.