Interferon-gamma is cytotoxic for normal mouse fibroblasts: enhancement by tumor necrosis factor and interleukin 1

Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are cytotoxic for certain tumor cells but have a proliferative effect on normal cells. Here we show that interferon-gamma (IFN-gamma) can be cytotoxic for normal cells, in particular mouse embryonic fibroblasts. The cytotoxicity effect is observed with immuno-purified recombinant mouse IFN-gamma (MuIFN-gamma) at concentrations of 1,000 I.U./ml and can be neutralized by anti-MuIFN-gamma monoclonal antibodies. The effect appears 48 h after initial contact with IFN-gamma and is not influenced by infection of the target cells with mengovirus. Although TNF and IL-1 are not toxic for mouse fibroblasts, they can strongly enhance the IFN-gamma-induced cytotoxicity. Interferon-alpha (IFN-alpha), interferon-beta (IFN-beta) and interleukin-6 (IL-6) neither are cytotoxic themselves nor have any influence on the IFN-gamma-induced cytotoxicity. The cytotoxicity of IFN-gamma, in contrast to that of TNF is inhibited by actinomycin or cycloheximide. These data suggest that the cytotoxic effect of IFN-gamma requires active cooperation of target cells and that the mechanism of action is different from that of the TNF-induced cytotoxicity.