Modulation of the growth of transformed cells by human tumor necrosis factor-alpha and interferon-gamma.

Recombinant human tumor necrosis factor-alpha (rHuTNF-alpha) inhibited growth of the cervical carcinoma cell line, ME-180neo, at doses greater than 50 units/ml, but stimulated the growth of these cells at low doses (0.1-10 units/ml). ME-180neo variants selected for resistance to the cytotoxic effects of rHuTNF-alpha retained the ability to be growth stimulated at all concentrations tested. ME-180neo cells and the rHuTNF-alpha-resistant ME-180neo variants possessed equivalent steady state numbers of TNF-alpha receptors with similar Kd values. Recombinant human interferon-gamma (rHuIFN-gamma) augmented the rHuTNF-alpha-induced cytotoxic response of ME-180neo cells and overcame the resistance of the ME-180neo variants to rHuTNF-alpha cytotoxicity. In separate experiments we were able to show that the number of TNF-alpha binding sites on both rHuTNF-alpha-sensitive and -resistant ME-180neo cells was similar and was increased by treatment with rHuIFN-gamma. These results suggest that the growth stimulation of tumor cells mediated by rHuTNF-alpha can be dissociated from the cytotoxic response and that these responses are not related to the number or affinity of TNF-alpha binding sites.