Systemic administration of IL-23 induces potent antitumor immunity primarily mediated through Th1-type response in association with the endogenously expressed IL-12
Systemic administration of IL-23 induces potent antitumor immunity primarily mediated through Th1-type response in association with the endogenously expressed IL-12
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DOI：
10.4049/jimmunol.178.12.7571
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发表时间：
2007-06-15
影响因子：
4.4
通讯作者：
Tahara, Hideaki
中科院分区：
文献类型：
--
作者：
Kaiga, Teruo;Sato, Marimo;Tahara, Hideaki
IL-23是一种细胞因子，由与IL-12和IL-23特异性p19亚基共享的p40亚基组成，已被证明优先作用于Th1效应/记忆CD4(+) T细胞，并诱导其增殖和ifn - γ的产生。IL-23也被报道作用于Th17-CD4(+) T细胞，参与诱导组织损伤。在本研究中，我们研究了IL-23在小鼠肿瘤系统中的抗肿瘤作用及其机制。通过在体内电穿孔IL-23质粒DNA进入C57BL/6小鼠的胫骨前肌肉，实现了全身给药高剂量IL-23。与用EGFP治疗的小鼠相比，IL-23治疗与先前存在的MCA205纤维肉瘤生长的显著抑制和治疗小鼠的生存期延长有关，而没有明显的毒性。虽然治疗结果与IL-12治疗相似，但IL-23治疗诱导的特征性免疫反应与IL-12治疗不同。即使在治疗水平的IL-23给药也没有诱导血清中可检测到的ifn - γ浓度。体内消耗CD4(+) T细胞、CD8(+) T细胞或NK细胞显著抑制IL-23的抗肿瘤作用。此外，il -23处理小鼠的淋巴结CD4(+) T细胞在体外抗cd3单抗刺激下表现出显著的ifn - γ和IL-17反应。这些结果以及在ifn - γ或IL-12基因敲除小鼠中的结果表明，当内源性表达的IL-12存在时，th1型反应被充分促进，IL-23治疗可以实现有效的抗肿瘤作用。
IL-23, a cytokine, which is composed of the p40 subunit shared with IL-12 and the IL-23-specific p19 subunit, has been shown to preferentially act on Th1 effector/memory CD4(+) T cells and to induce their proliferation and IFN-gamma production. The IL-23 is also reported to act on Th17-CD4(+) T cells, which are involved in inducing tissue injury. In this study, we examined the antitumor effects associated with systemic administration of IL-23 and their mechanisms in mouse tumor system. Systemic administration of high-dose IL-23 was achieved using in vivo electroporation of IL-23 plasmid DNA into the pretibial muscles of C57BL/6 mice. The IL-23 treatment was associated with significant suppression of the growth of pre-existing MCA205 fibrosarcoma and prolongation of the survival of treated mice without significant toxicity when compared with those of the mice treated with EGFP. Although the therapeutic outcomes were similar to those with the IL-12 treatment, the IL-23 treatment induced characteristic immune responses distinctive to those of IL-12 treatment. The IL-23 administration even at the therapeutic levels did not induce detectable IFN-gamma concentration in the serum. In vivo depletion of CD4(+) T cells, CD8(+) T cells, or NK cells significantly inhibited the antitumor effects of IL-23. Furthermore, the CD4(+) T cells in the lymph nodes in the IL-23-treated mice showed significant IFN-gamma and IL-17 response upon anti-CD3 mAb stimulation in vitro. These results and the ones in the IFN-gamma or IL-12 gene knockout mice suggest that potent antitumor effects of IL-23 treatment could be achieved when the Th1-type response is fully promoted in the presence of endogenously expressed IL-12.