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

IL-18抗肿瘤作用研究-CD11b启动子基因IL-18转基因小鼠分析

基本信息

批准号：
17591450
负责人：
SEKI Naoko
金额：
$ 2.18万
依托单位：
Kurume University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591450/
关键词：
Cancer Immunology

项目摘要

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.

IL-18是一种I型细胞因子，以前被鉴定为IFN-γ诱导因子。IL-18具有多种免疫应答作用，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，J Immunol，1999/ Eur J Immunol，2000等）。在本研究中，我们研究了IL-18在小鼠模型中的抗肿瘤作用的机制。IL-18能有效诱导肿瘤特异性T细胞，促进DC成熟。这些效应T细胞增加死亡配体-FasL和TRAIL-表达与IL-18刺激，增强FasL介导的细胞毒性对肿瘤细胞和内皮细胞作为旁观者效应。本研究建立了在CD 11b启动子基因调控下表达小鼠IL-18成熟cDNA的转基因（Tg）小鼠，并进行了体内实验研究。然而，这些Tg小鼠可以表达非常低水平的IL-18在其血清和上清液从LPS刺激的PEC。现在，我们将使用另一种具有Ig启动子的IL-18 Tg小鼠品系进行进一步的体内分析，其中已经报道了高水平的IL-18产生（Hoshino等人，J Immunol，2001）。用Tg小鼠进行的体内研究可以给出IL-18的抗肿瘤作用的许多方面。