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目的探讨IL-18抑制人肝癌裸鼠皮下移植瘤进展的机制。方法选用人肝癌细胞株HepG2建立裸鼠皮下移植瘤模型,予IL-181.25μg。分4 w组、3 w组、2 w组和0 w组,其中4 w组为模型开始建立的第1天始注射IL-18,注射时间为0～4 w;3 w组为模型开始建立后1 w始注射IL-18,注射时间为1～4 w;2 w组为模型开始建立后1 w始注射IL-18,注射时间为1～3 w,第4 w停止治疗;0 w组为模型建立4周均未注射IL-18的对照组。4 w后处死取肿瘤组织,免疫磁珠阴选各组肿瘤组织中CD4+T细胞,流式细胞术检测各组浸润的CD4+T细胞中IL-17+CD4+T(Th17)细胞和IFN-γ+、CD4+T(Th1)细胞水平。结果 IL-18能显著抑制肝癌皮下移植瘤的形成及转移,早期给药疗效更佳,随着疗程的延长肿瘤逐渐减小;IL-18给药疗程越长,肿瘤组织中浸润的Th1细胞越多,Th17细胞减少,4 w组与0 w组比较差异显著(P<0.01),3 w组、2 w组与0 w组比较差异显著(P<0.05);IFN-γ生成和IL-17减少与细胞表达一致。结论 IL-18诱导IFN-γ的生成,抑制IL-17的产生,减少Th17细胞的分化,抑制肿瘤微环境中新生血管的形成和肿瘤的进展;在肿瘤微环境中,IFN-γ产生增强了细胞毒作用及机体对肿瘤细胞的免疫监视功能。
Objective To investigate the mechanism of IL-18 inhibiting the progress of human hepatocellular carcinoma xenografts in nude mice. Methods Human hepatocellular carcinoma cell line HepG2 was used to establish a subcutaneous xenograft tumor model in nude mice, which was treated with IL-181.25μg. The rats were divided into 4w, 3w, 2w and 0w groups. The 4w group started injection of IL-18 on the first day and the injection time was 0-4w. The 3w group started to establish IL-18 was injected 1 h after injection, and the injection time was 1 ~ 4 w. IL-18 was injected 1 w after the start of the model in the 2 w group, and the injection time was 1 ~ 3 w, The model was established 4 weeks were not injected IL-18 control group. After 4 w, the tumor tissues were sacrificed and immunomagnetic beads were used to screen the CD4 + T cells in the tumor tissue. The number of IL-17 + CD4 + T (Th17) cells and IFN-γ in the infiltrating CD4 + T cells were detected by flow cytometry -γ +, CD4 + T (Th1) cells. Results IL-18 could significantly inhibit the formation and metastasis of subcutaneously transplanted hepatocellular carcinoma. The efficacy of early administration was better, and the tumor gradually decreased with prolonged course of treatment. The longer the course of IL-18 administration, the more infiltrated Th1 cells in tumor tissue (P <0.01). There was significant difference between 3 w and 2 w groups and 0 w group (P <0.05). The levels of IFN-γ and IL-17 Reduce the same with cell expression. Conclusion IL-18 induces the production of IFN-γ, inhibits the production of IL-17, decreases the differentiation of Th17 cells, inhibits the formation of neovascularization and tumor progression in the tumor microenvironment, and enhances the production of IFN-γ in the tumor microenvironment Cytotoxicity and the body’s immune surveillance of tumor cells.