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

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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.