Effect of interleukin-18 on metastasis of mouse osteosarcoma cells

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Osteosarcoma is the most common primary malignant bone tumor. Metastasis mostly in the lung invariably affects patient's survival. Therefore, the suppression of pulmonary metastasis is one of the most important issues in the treatment of osteosarcomas.Interleukin-18 (IL-18), previously called interferon-γ (IFN-γ )-inducing factor, exerts an anti-tumor action through activation of natural killer cells (NK cells) or cytotoxic T lymphocytes, suppression of angiogenesis and induction of Fas-ligand on tumor cells expressing Fas. We have shown that IL-18 inhibits the growth of osteosarcoma cells by activating T lymphocytes, suggesting the usefulness of IL-18 as a therapy agent for osteosarcoma. In this study, we examined the effect of IL-18 on pulmonary metastasis of osteosarcoma using an experimental metastasis model in which highly metastatic LM8 mouse osteosarcoma cells were injected into a tail vein of T cell-deficient nude mice treated with anti-asialo GM1 serum to abolish the activity of NK cells. We found that IL-18 inhibited metastasis of osteosarcoma cells partly by inducing a factor(s) in the host which suppressed mobility of LM8 cells.α-Galactosylceramide (α-GalCer) is known as antitumor agent by activating NK cells. We also found IL-18 in conjunction with α-GalCer exerts an antitumor effect on NK cell-sensitive tumors primarily by the direct stimulation of NK cells by IL-18 and the indirect stimulation of NK cells by α-GalCer through its activation of NKT cells.