Interleukin 4 potentiates the antiproliferative effects of tumor necrosis factor on various tumor cell lines.

In response to a given stimulus, usually a number of cytokines are secreted simultaneously by the immune system. Whether these cytokines are meant to function as a single agent or in combination with others is not understood. Tumor necrosis factor (TNF) has been shown to exhibit antiproliferative effects against a wide variety of tumor cell lines in vitro. In the present report, we investigated the effects of a T-cell-derived cytokine, interleukin 4 (IL-4), on the antiproliferative effects of TNF against different tumor cell lines. The growth characteristics of human breast cancer cells (MDA-MB-330) were minimally affected when the cells were exposed to either TNF or IL-4 alone. However, together these 2 cytokines inhibited cell growth in a dose-dependent manner. The enhancement of the cytotoxic effects of TNF by IL-4 were not just limited to breast tumor cells, but were also observed with human epidermoid carcinoma cells (A-431) and human histiocytic lymphoma cells (U-937). The enhancement of the cytotoxic effect of TNF by IL-4 against various tumor cell lines was found comparable with that by gamma-interferon (IFN-gamma). Interestingly, for certain tumor cell types, IL-4 alone was found to enhance cell proliferation. IL-4 had no effect on the growth-stimulatory activity of TNF on normal human foreskin fibroblasts. Pre-exposure of U-937 cells to IFN-gamma led to a greater than 2-fold induction in TNF receptors, but no modulation of TNF receptors by IL-4 was observed. Moreover, the presence of IFN-gamma was found to further potentiate the antiproliferative effects of TNF and IL-4. These results clearly suggest that IL-4 potentiates the antiproliferative responses of TNF by a mechanism different from that of IFN-gamma. Although it is well known that IL-4 can modulate the production of TNF from macrophages, this is the first report to suggest that IL-4 can also modulate TNF-dependent antiproliferative responses.