Chang Chi-Young, Lee Jienny, Kim Eun-Young, Park Hae-Jung, Kwon Choon-Hyuck, Joh Jae-Won, Kim Sung-Joo
Transplantation Research Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Kangnam-Ku, Seoul, Republic of Korea.
BMC Cancer. 2007 May 23;7:87. doi: 10.1186/1471-2407-7-87.
The novel cytokine, interleukin (IL)-18, is a strong interferon-gamma inducer and costimulatory factor in Th1 cell activation. IL-18 triggers IFN-gamma production and enhances cytolytic activity in both T and NK cells. However, the exact mechanism of antitumor action of IL-18 remains to be clarified. To determine the effects of IL-18 plasmid DNA on hepatic cancer in mice, CT26 murine colon adenocarcinoma cells were established in mouse liver.
Plasmid vectors encoding IL-18 were transferred directly into the liver 7 days after tumor injection to restrict IL-18 expression within the tumor site. The IL-18 protein level was increased in the liver 4 days after plasmid injection, and a marked antitumoral effect was observed at day 7. Antitumor effects were evaluated by measuring tumor regression, immune cell population, and IFN-gamma production.
The IL-18 plasmid controlled the growth of hepatic tumors and proliferation of splenic immune cells. Moreover, treatment of CT26 tumors with the IL-18 plasmid significantly enhanced the population of the effector T and NK cells in the spleen and peripheral blood. In spleen, the population of CD4+CD62Low cells was augmented in response to IL-18 on day 7. These results are consistent with the increase in CD4+ T cells secreting IFN-gamma, but not CD8+ T cells. The marked reduction of tumor growth in tumor-bearing mice was associated with the maintenance of IFN-gamma production in spleen in response to IL-18. These antitumoral effects were maintained until 14 days after plasmid injection.
Our results suggest that direct plasmid DNA transfer of IL-18 with no accompanying reagents to augment transfection efficiency may be useful in tumor immunotherapy.
新型细胞因子白细胞介素（IL）-18是一种强大的干扰素-γ诱导剂，也是Th1细胞激活中的共刺激因子。IL-18可触发IFN-γ的产生，并增强T细胞和NK细胞的细胞溶解活性。然而，IL-18抗肿瘤作用的确切机制仍有待阐明。为了确定IL-18质粒DNA对小鼠肝癌的影响，将CT26小鼠结肠腺癌细胞接种到小鼠肝脏中。
在肿瘤接种7天后，将编码IL-18的质粒载体直接注射到肝脏中，以限制IL-18在肿瘤部位的表达。质粒注射4天后，肝脏中IL-18蛋白水平升高，在第7天观察到明显的抗肿瘤作用。通过测量肿瘤消退、免疫细胞群体和IFN-γ产生来评估抗肿瘤作用。
IL-18质粒可控制肝肿瘤的生长和脾免疫细胞的增殖。此外，用IL-18质粒处理CT26肿瘤可显著增加脾脏和外周血中效应T细胞和NK细胞的数量。在脾脏中，第7天CD4+CD62Low细胞群体因IL-18而增加。这些结果与分泌IFN-γ的CD4+T细胞增加一致，而CD8+T细胞未增加。荷瘤小鼠肿瘤生长的显著减少与脾脏中因IL-18而维持的IFN-γ产生有关。这些抗肿瘤作用一直维持到质粒注射后14天。
我们的结果表明，在不使用辅助试剂提高转染效率的情况下直接进行IL-18质粒DNA转移可能对肿瘤免疫治疗有用。
