Study on anti-tumor effects of IL-18-analysis of IL-18 transgenic mouse with CD11b promoter gene

IL-18是I型细胞因子之一，先前被鉴定为IFN-γ诱导因子。IL-18对免疫应答有多种影响，包括刺激自然杀伤细胞（NK）和T/B淋巴细胞产生高水平的IFN-γ和IL-2，促进T细胞增殖，增强细胞毒性T淋巴细胞（CTL）和NK细胞的杀伤活性。我们也报道了IL-18的多种生理功能，以及与皮肤和呼吸系统疾病的关联（Hoshino等）。免疫学杂志，1999/欧洲免疫学杂志，2000等)。在本研究中，我们在小鼠模型中研究了IL-18抗肿瘤作用的机制。IL-18可诱导肿瘤特异性T细胞，有效促进DC成熟。这些效应T细胞在IL-18刺激下增加死亡配体fasl和trail的表达，增强fasl介导的对肿瘤细胞和内皮细胞的细胞毒性。提示免疫效应细胞诱导肿瘤排斥反应不仅可以直接杀伤肿瘤细胞，还可以对肿瘤环境产生影响，包括肿瘤源性血管生成。本研究建立了成熟小鼠IL-18 cDNA在CD11b启动子基因控制下表达的转基因（Tg）小鼠，以便在体内进行分析。然而，这些Tg小鼠在lps刺激的PEC的血清和上清中表达非常低水平的IL-18。现在，我们将使用另一株具有ig -启动子的IL-18 Tg小鼠在体内进一步分析，其中已经报道了高水平的IL-18产生（Hoshino等）。免疫学杂志，2001)。在Tg小鼠体内研究IL-18的抗肿瘤作用。

IL-18, previously identified as IFN-γ-inducing factor, is one of type I cytokines. IL-18 elicits a variety of effects on immune response, including stimulating natural killer cells (NK) and T/B lymphocytes to produce high levels of IFN-γ and IL-2, promoting T cell proliferation, enhancing killing activity of cytotoxic T lymphocytes (CTL) and NK cells. We have also reported a variety of physiological function of IL-18, and association with diseases on skin and respiratory system (Hoshino et al. J Immunol, 1999/ Eur J Immunol, 2000, etc). In this study, we investigated mechanisms of anti-tumor effects with IL-18 in mouse model. IL-18 could induce tumor specific T cells efficiently facilitating DC maturation. These effector T cells increased death ligands-FasL and TRAIL-expression with IL-18 stimulation, potentiating FasL-mediated cytotoxicity against tumor cells and also endothelial cells as bystander effects. This result suggests that tumor rejection would be induced by immune effector cells not only due to direct killing of tumor cells, but also effects to tumor environment including tumor derived angiogenesis.In this study, we established transgenic (Tg) mouse, in which mature mouse IL-18 cDNA is expressed under the control of CD11b promoter gene, in order to in vivo analysis. However, these Tg mice could express very low levels of IL-18 in their serum and supernatant from LPS-stimulated PEC. Now we are going to further analysis in vivo using another strain of IL-18 Tg mouse with Ig-promoter, in which high level of IL-18 production has been reported (Hoshino et al. J Immunol, 2001). In vivo study with the Tg mouse could give many aspects on anti-tumor effects with IL-18.