Effect of interleukin-18 on metastasis of mouse osteosarcoma cells

骨肉瘤是最常见的原发性恶性骨肿瘤。转移主要发生在肺部，影响患者的生存。因此，抑制肺转移是骨肉瘤治疗中最重要的问题之一。白介素18(IL-18)，以前被称为干扰素-γ(干扰素-γ)诱导因子，通过激活自然杀伤细胞(NK细胞)或细胞毒性T淋巴细胞、抑制血管生成和诱导Fas配体在表达Fas的肿瘤细胞上发挥抗肿瘤作用。我们发现IL-18通过激活T淋巴细胞抑制骨肉瘤细胞的生长，提示IL-18作为骨肉瘤的治疗药物是有用的。在这项研究中，我们通过将高转移的LM8小鼠骨肉瘤细胞注射到T细胞缺陷裸鼠的尾静脉中，用抗asialo GM1抗血清来消除NK细胞的活性，观察了IL-18对骨肉瘤肺转移的影响。我们发现IL-18抑制骨肉瘤细胞的转移部分是通过在宿主体内诱导一种抑制LM8细胞迁移的因子(S)来实现的，α-半乳糖基神经酰胺(α-GalCer)是通过激活NK细胞而被认为是抗肿瘤药物。我们还发现IL-18联合α-GalCer对NK细胞敏感的肿瘤具有抗肿瘤作用，主要是通过IL-18直接刺激NK细胞和α-GalCer通过激活NKT细胞间接刺激NK细胞。

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.