APOPTOSIS - A NEW MECHANISM OF ENDOTHELIAL AND KUPFFER CELL-KILLING

Kupffer cells (KC) become activated in response to lipopolysaccharide (LPS) and produce a variety of mediators. Among them, TNFalpha is know n to injure the liver. Here we report that TNFalpha mediates apoptosis in KC and sinusoidal endothelial cells. After stimulation for 24 h wi th LPS (0-10 mu g/mL), apoptosis in KC detected by TUNEL TdT-mediated dUTP-biotin nick end labelling (TUNEL) increased in a concentration-de pendent manner (0 mu g/mL, 12+/-4%; 0.1 mu g/mL, 36+/-11%; 1.0 mu g/mL , 65+/-9%; 10 mu g/mL, 78+/-15%). In contrast, co-incubation of endoth elial cells with LPS-stimulated KC resulted in a marked increase in TU NEL-positive endothelial cells. TNFalpha antibody blocked apoptosis in both KC and endothelial cells. Apoptosis was observed in cells adjace nt to or in contact with KC. Reducing transmembrane TNFalpha expressed on KC also led to a decrease in endothelial cell apoptosis, suggestin g that transmembrane TNFalpha is implicated in the cell-to-cell contac t mechanism of induction of apoptosis. Thus, TNFalpha mediates apoptos is in KC and endothelial cells.