MONOCYTE ROLLING, ARREST AND SPREADING ON IL-4-ACTIVATED VASCULAR ENDOTHELIUM UNDER FLOW IS MEDIATED VIA SEQUENTIAL ACTION OF L-SELECTIN, BETA(1)-INTEGRINS, AND BETA(2)-INTEGRINS

Leukocyte interactions with vascular endothelium at sites of inflammat ion can be dynamically regulated by activation-dependent adhesion mole cules. Current models, primarily based on studies with polymorphonucle ar leukocytes, suggest the involvement of multiple members of the sele ctin, integrin, and immunoglobulin gene families, sequentially, in the process of initial attachment (rolling), stable adhesion (arrest), sp reading and ultimate diapedesis. In the current study, IL-4-activated human umbilical vein endothelium, which selectively expresses VCAM-1 a nd an L-selectin ligand but not E-selectin, and appropriate function b locking monoclonal antibodies, were used to study monocyte-endothelial interactions in an in vitro model that mimics microcirculatory flow c onditions. In this system, L-selectin mediates monocyte rolling and al so facilitates alpha(4) beta(1)-integrin-dependent arrest, whereas bet a(2)-integrins are required for spreading of firmly attached monocytes on the endothelial cell surface but not their arrest. These findings provide the first in vitro evidence for human monocyte rolling on cyto kine-activated endothelium, and suggest a sequential requirement for b oth beta(1)- and beta(2)-integrin-dependent adhesive mechanisms in mon ocyte-endothelial interactions.