Nishihori H, Tsuji H, Wang H, Tahara H, Akiyama M, Ogawa Y, Matsushima K, Iwakura Y, Mukaida N
Department of Molecular Oncology, Cancer Research Institute, Kanazawa University, Japan.
Hum Gene Ther. 2000 Mar 20;11(5):659-68. doi: 10.1089/10430340050015563.
To elucidate the molecular mechanism underlying IL-4-induced tumor rejection, we challenged mice with a mouse adenocarcinoma cell line, colon 26, genetically engineered to express constitutively IL-4 gene (colon 26/IL-4). Immunocompetent BALB/c mice rejected colon 26/IL-4 cells but not parental cells or cells transduced with a control gene (colon 26/control). Moreover, on rechallenge, parental cells and colon 26/control cells were rejected by normal BALB/c mice that had previously rejected colon 26/IL-4. However, both nude and severe combined immunodeficiency (SCID) mice failed to reject colon 26/IL-4 as well as parental or colon 26/control cells. In contrast, nude mice did reject colon 26/IL-4 after transfer of lymphocytes obtained from the draining lymph nodes of BALB/c mice injected with colon 26/IL-4. These results indicate that challenging mice with colon 26/IL-4 tumor cells resulted in the generation of memory cytotoxic T lymphocytes in the draining lymph nodes. At 3 days after the challenge, IFN-gamma, IL-12 p35, and p40 mRNA expression was selectively enhanced in the draining lymph nodes of mice bearing colon 26/IL-4 cells. Finally, mice deficient in the IFN-gamma gene did not reject colon 26/IL-4 cells. These results suggest that IL-4-induced memory cytotoxic T lymphocyte generation requires IFN-gamma production in the draining lymph nodes, in order to generate a protective immune response.
为阐明白细胞介素-4（IL-4）诱导肿瘤排斥反应的分子机制，我们用一种经基因工程改造以组成性表达IL-4基因的小鼠腺癌细胞系结肠26（colon 26/IL-4）对小鼠进行攻击。具有免疫活性的BALB/c小鼠排斥结肠26/IL-4细胞，但不排斥亲代细胞或转导了对照基因的细胞（结肠26/对照）。此外，再次攻击时，亲代细胞和结肠26/对照细胞被先前排斥过结肠26/IL-4的正常BALB/c小鼠排斥。然而，裸鼠和严重联合免疫缺陷（SCID）小鼠均未能排斥结肠26/IL-4以及亲代或结肠26/对照细胞。相反，在注射了结肠26/IL-4的BALB/c小鼠引流淋巴结中获取淋巴细胞并转移给裸鼠后，裸鼠确实排斥了结肠26/IL-4。这些结果表明，用结肠26/IL-4肿瘤细胞攻击小鼠导致在引流淋巴结中产生记忆性细胞毒性T淋巴细胞。攻击后3天，在携带结肠26/IL-4细胞的小鼠引流淋巴结中，干扰素-γ（IFN-γ）、白细胞介素-12 p35和p40的mRNA表达选择性增强。最后，缺乏IFN-γ基因的小鼠不能排斥结肠26/IL-4细胞。这些结果表明，IL-4诱导的记忆性细胞毒性T淋巴细胞生成需要在引流淋巴结中产生IFN-γ，以产生保护性免疫反应。
