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

IL-18是一种I型细胞因子，以前被认为是干扰素-γ诱导因子。IL-18可诱导多种免疫应答，包括刺激自然杀伤细胞(NK)和T/B淋巴细胞产生高水平的干扰素-γ和IL-2，促进T细胞增殖，增强细胞毒性T细胞和NK细胞的杀伤活性。我们还报道了IL-18的多种生理功能，以及与皮肤和呼吸系统疾病的关系(Hoshino等人)。J免疫，1999/欧盟J免疫，2000年等)。本研究以小鼠为研究对象，探讨了IL-18抗肿瘤作用的机制。IL-18可有效诱导肿瘤特异性T细胞，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，增强了FasL介导的对肿瘤细胞的细胞毒作用，也增强了作为旁观者的内皮细胞的作用。这一结果表明，免疫效应细胞不仅通过直接杀伤肿瘤细胞而诱导肿瘤排斥反应，而且还会对肿瘤环境包括肿瘤血管生成产生影响。本研究建立了在CD11b启动子基因控制下表达成熟小鼠IL-18的转基因(TG)小鼠，以进行体内分析。然而，这些转基因小鼠可以在其血清和内毒素刺激的PEC培养上清液中表达极低水平的IL-18。现在，我们将使用另一株带有Ig启动子的IL-18 TG小鼠在体内进行进一步的分析，其中已报道有高水平的IL-18产生(Hoshino等人)。《免疫杂志》，2001)。用Tg小鼠进行体内研究可以从多个方面研究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.