POLAR AGENTS WITH DIFFERENTIATION-INDUCING CAPACITY POTENTIATE TUMOR NECROSIS FACTOR-MEDIATED CYTOTOXICITY IN HUMAN MYELOID CELL-LINES

Cotreatment or pretreatment of several human myeloid cell lines (KG1, HL60, U937, THP1) with the differentiation inducer DMSO was found to p otentiate the antiproliferative and cytotoxic effects of TNF. In addit ion, TNF-resistant monocytic cell lines could be sensitized to TNF cyt otoxicity by DMSO treatment. Other highly polar molecules, known to be potent differentiation inducers, showed similar effects to those of D MSO. The potentiating effect of DMSO was related neither to an up-regu lation of TNF receptor expression nor to an alteration in the rate of TNF internalization and degradation. We present evidence that the TNF activities are p55 TNF receptor-mediated and are not due to insertion of TNF into lipid bilayers, an effect that could be susceptible to DMS O, as this component has been described to modify cell membrane charac teristics. DMSO-induced potentiation of TNF cytostasis/cytotoxicity wa s restricted to myeloid leukemia cell lines. In non-myeloid cells such as fibrosarcomas, myosarcomas, thymomas, or carcinomas, DMSO was foun d either not to alter or to inhibit TNF-induced cell death. The latter results are in good agreement with data reported by others who sugges ted that DMSO could act as a scavenger of TNF-induced toxic radical fo rmation. The potential correlation in myeloid cells between DMSO-induc ed changes in the cells' differentiation status and DMSO-enhanced TNF- susceptibility is discussed.