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The mechanism by which tumor necrosis factor alpha (TNF) initiates tumor cell destruction is unknown. Having established that a brief drop in extracellular pH enhances the killing activity of TNF, our next objective was to explore whether TNF-induced cell death is dependent on endosomal acidification. Diphtheria toxin (DTx), a well-characterized acid-dependent cytotoxin, served as an indicator of the effectiveness of each treatment condition. Studies with lysosomotropic agents demonstrated that the cytotoxic pathway of TNF can operate independently of low pH exposure in contrast to the lethal pathway of DTx. When NH4Cl-treated cells were exposed to TNF at low pH, the level of killing increased two- to threefold over that attained with cells maintained at neutral pH (either with or without NH4Cl). Furthermore, inhibition of metabolic processes by sodium azide in combination with 2-deoxyglucose severely reduced DTx killing but stimulated TNF killing. Despite these differences, TNF and DTx provoked extensive internucleosomal DNA cleavage in prelytic target cells. Inhibitor of nuclear poly(ADP-ribose) transferase also evoked similar levels of cellular resistance to both cytotoxins. Models for DTx- and TNF-induced cytolysis are discussed in view of these new discoveries.

Comparison of the intoxication pathways of tumor necrosis factor and diphtheria toxin