ACTIVATION OF TNF-R1 RECEPTOR IN THE PRESENCE OF COPPER KILLS TNF RESISTANT CEM LEUKEMIC T-CELLS

The cytotoxic effects of TNF on malignant cells are known to be mediat ed through high affinity surface receptors. The precise mechanism by w hich transformed cells are selectively killed by the activation of the se receptors is yet unknown, but several intracellular signaling pathw ays are known to be involved. Phospholipase A2 activation by TNF-alpha has been shown to be important in the transduction of signals leading to cell death. We have used monitoring of extracellular acidification rate as a measure of cellular metabolism to follow the early time cou rse of TNF effects on a human leukemic T cell line (CEM-SS cells). CEM -SS cells were relatively resistant to TNF cell killing but TNF caused an early stimulation of metabolism within 2-4 hr, followed by a suppr ession of metabolic activity occurring over 20 hr. In contrast, a TNF sensitive subclone of CEM cells (C1 Ca) showed a rapid and dramatic de crease in metabolic activity corresponding to cytotoxicity within 18 h r. It was discovered that cupric o-phenanthroline markedly potentiated the effects of TNF on the resistant CEM-SS cells leading to cell deat h. This observation was specific for copper because ferric o-phenanthr oline was without effect at the same concentration. The copper cytotox ic effect was shown to be mediated through the TNF-R1 receptor and ind ependent of phospholipase A2 signaling. (C) 1994 Wiley-Liss, Inc.