APOPTOSIS OF ENDOTHELIAL-CELLS IS ASSOCIATED WITH PARACRINE INDUCTIONOF ADHESION MOLECULES - EVIDENCE FOR AN INTERLEUKIN-1-BETA-DEPENDENT PARACRINE LOOP

Monocytic infiltration of the vessel wall is a hallmark of injury in a variety of vascular diseases. In the present study, we explored the r elationship between endothelial apoptosis and hyperadhesiveness for mo nocytic cells. Apoptosis of human umbilical vein endothelial cells (HU VECs) was induced by either growth factor deprivation (GFD) for 24 hou rs or by incubation with mitomycin C (MMC) at 0.01 mg/ml for 24 hours and confirmed by light microscopy and DNA laddering. In parallel asses sments of cell-cell adhesion, GFD and MMC induced hyperadhesiveness of HUVECs for the THP-1 monocytic cell line. Hyperadhesiveness developed in association with induction of intercellular adhesion molecule (ICA M)-1 and vascular cell adhesion molecule (VCAM)-1 on HUVECs and was at tenuated by monoclonal antibodies directed against these ligands. Cult ure medium conditioned by apoptotic HUVECs up-regulated the expression of adhesion molecules on normal HUVECs, suggesting that paracrine fac tors in the apoptotic milieu led to induction of adhesion molecules. I nterleukin (IL)-1 beta was implicated as a putative mediator in this s etting because 1) exogenous IL-1 beta up-regulates ICAM-1 and VCAM-1 w ith kinetics similar to those noted during endothelial cell apoptosis, 2) endothelial apoptosis was associated with increased expression of IL-1 beta converting enzyme, and 3) the adhesion-promoting actions of GFD and MMC were attenuated by an anti-IL-1 beta antibody.