VLA-4 integrin can mediate CD11/ CD18-independent transendothelial migration of human monocytes

The migration of human monocytes across unactivated and ac-tivated human umbilical vein endothelium (HUVE) in response to chemotactic factors was studied, and the adhesion molecules involved were characterized. Migration of blood monocytes or U937 cell line-derived monocytes across unactivated HUVE induced by C5a, was partially inhibited (by 75%) by mAbs (R15.7 or 60.3) to CD18 of the CD11/CD18 complex on the monocyte. However, when the HUVE was pretreated for 5 h with IL-la (0.1 ng/ml), TNF-a (100 U/ml), or LPS (1 ng/ml), migration induced by C5a was no longer inhibited; i.e., migra-tion became CD18 independent. The monocyte CD18-indepen-dent migration was completely blocked by mAbs against a4 or 01 integrin chains of VLA4. This migration was also partially inhibited by mAbs against vascular cell adhesion molecule-i (VCAM-1), a major counter-receptor on HUVE for VLA4, but not by mAbs to E-selectin or intercellular adhesion mole-cule-i. The significant CD18-independent migration across "unactivated " HUVE was also inhibited by mAbs against a4 or #I chains of VLA4, although mAbs against VCAM-1 did not inhibit under these conditions. Finally, considerable VLA4-dependent transendothelial migration to C5a was also observed with monocytes from a patient with CD18 deficiency (leukocyte adhesion deficiency). These results suggest that (a) there is a major CD18-independent component in monocyte chemotactic factor-dependent migration across activated and unactivated en-dothelium; (b) that VLA4 integrin on the monocyte has a ma-jor role in this migration; and (c) that VCAM-1 on activated endothelium functions as a counter-receptor in this process, but other ligands for VLA4, especially on unactivated endothe