Protection from tumor necrosis factor cytotoxicity by protease inhibitors

Tumor necrosis factor (TNF) is cytocidal for human and murine cells when protein synthesis is inhibited by cycloheximide, but some protease inhibitors completely protect these cells from TNF cytotoxicity. Inhibitors of chymotrypsin-like proteases are active at lower concentrations than inhibitors of trypsin-like proteases. Both irreversible inhibitors, such as alkylating compounds, and reversible inhibitors, such as substrates of proteases, protect cells from the cytocidal activity of TNF. This protection is most effective when the cells are pretreated with these inhibitors before addition of TNF. When the protease inhibitors are removed, the cells gradually lose resistance to TNF cytotoxicity. The inhibitors do not interfere with the functioning of TNF-receptor complexes, since SK-MEL-109 melanoma cells treated with a protease inhibitor synthesize a TNF-induced protein. These findings suggest that a protease in involved in the cytocidal action of TNF.