TNF-mediated cytotoxicity. Importance of intracellular cGMP level for determining TNF-sensitivity

Previous work on the cytolytic action of activated macrophages indicated that tumor necrosis factor (TNF) showed synergistic cytolytic activity with NO, which has been shown to act as a cyclic GMP (cGMP) generator [Higuchi et al., J. Immun. 144, 1425-1431, (1990)]. In this study, we investigated the relationship between the accumulation of intracellular cGMP and the cytotoxic action of TNF. It was demonstrated that TNF-mediated cell lysis was closely related to the background level of intracellular cGMP, and that the accumulation of cGMP within TNF resistant cells induced TNF sensitivity. We reached these conclusions on the basis of the following results; (1) agents (sodium nitroprusside and isobutylmethylxantine) that cause the accumulation of cGMP intracellularly increased the TNF-sensitivity of TNF-resistant cells; (2) the addition of dibutyryl cGMP to TNF-resistant cells increased the TNF-sensitivity; and (3) treatment at 40 degrees C or agents such as interferon gamma and actinomycin D, that synergistically kill tumor cells together with TNF, potentially increased the cGMP level. Therefore, intracellular cGMP may be one of the key molecules that lead to cell death caused by TNF.