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Interleukin 18 (IL-18) reportedly synergizes with IL-12 and IL-10 for interferon gamma (IFN-gamma) synthesis and natural killer (NK) cell activity, respectively. Here we show that IL-18 alone induces low level IFN-gamma production by unstimulated Balb/c mouse spleen cells, but production is enhanced synergistically in cocultures of spleen cells and allogeneic living or fixed Yac-1 cells. Spleen cells could be primed with IL-18 prior to coculture with Yac-1 cells for IFN-gamma production, which also was observed in cocultures containing either syngeneic or xenogeneic tumor cells. IFN-gamma production in stimulated cocultures was abrogated almost completely by anti-IL-12 antibody and was unrelated to spleen cell lytic activity. IL-10 moderately inhibited IFN-gamma production induced by IL-18. Therefore, in spleen cell and tumor cell cocultures exposed to IL-18, high levels of IFN-gamma are produced by the spleen cells arising from a synergistic interaction between the exogenous IL-18 and endogenous IL-12; however, this activity is unrelated to the spleen cell lytic activity.

Artepillin C was extracted from Brazilian propolis. Artepillin C (3,5-diprenyl-4-hydroxycinnamic acid) has a molecular weight of 300.40 and possesses antibacterial activity. When artepillin C was applied to human and murine malignant tumor cells in vitro and in vivo, artepillin C exhibited a cytotoxic effect and the growth of tumor cells was clearly inhibited. The artepillin C was found to cause significant damage to solid tumor and leukemic cells by the MTT assay, DNA synthesis assay, and morphological observation in vitro. When xenografts of human tumor cells were transplanted into nude mice, the cytotoxic effects of artepillin C were most noticeable in carcinoma and malignant melanoma. Apoptosis, abortive mitosis, and massive necrosis combined were identified by histological observation after intratumor injection of 500 microg of artepillin C three times a week. In addition to suppression of tumor growth, there was an increase in the ratio of CD4/CD8 T cells, and in the total number of helper T cells. These findings indicate that artepillin C activates the immune system, and possesses direct antitumor activity.