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, TNF alpha is known to injure the liver. Here we report that TNF alpha mediates apoptosis in KC and sinusoidal endothelial cells. After stimulation for 24 h with LPS (0-10 micrograms/mL), apoptosis in KC detected by TUNEL TdT-mediated dUTP-biotin nick end labelling (TUNEL) increased in a concentration-dependent manner (0 micrograms/mL, 12 +/- 4%; 0.1 microgram/mL, 36 +/- 11%; 1.0 micrograms/mL, 65 +/- 9%; 10 micrograms/mL, 78 +/- 15%). In contrast, co-incubation of endothelial cells with LPS-stimulated KC resulted in a marked increase in TUNEL-positive endothelial cells. TNF alpha antibody blocked apoptosis in both KC and endothelial cells. Apoptosis was observed in cells adjacent to or in contact with KC. Reducing transmembrane TNF alpha expressed on KC also led to a decrease in endothelial cell apoptosis, suggesting that transmembrane TNF alpha is implicated in the cell-to-cell contact mechanism of induction of apoptosis. Thus, TNF alpha mediates apoptosis in KC and endothelial cells.