IL-23 suppresses innate immune response independently of IL-17A during carcinogenesis and metastasis
IL-23 suppresses innate immune response independently of IL-17A during carcinogenesis and metastasis
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DOI：
10.1073/pnas.1003251107
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发表时间：
2010-05-04
影响因子：
11.1
通讯作者：
Smyth, Mark J.
中科院分区：
文献类型：
--
作者：
Teng, Michele W. L.;Andrews, Daniel M.;Smyth, Mark J.
IL-23是Th 17细胞的重要分子驱动因子，并且具有强烈的促肿瘤促炎活性，推测其通过适应性免疫发生。相反，最近有报道称，IL-17 A可激发保护性炎症，促进肿瘤特异性CD 8（+）T细胞的活化。在这里，我们显示了IL-23在拮抗主要由先天免疫介导的抗肿瘤免疫应答中的更广泛的影响。此外，这种影响的大部分与IL-17 A无关，IL-17 A对于许多宿主对肿瘤起始或转移的反应似乎并不关键。在宿主NK细胞控制疾病的三种模型中，IL-23缺陷型小鼠对实验性肿瘤转移具有抗性。用IL-2进行的免疫治疗在缺乏IL-23的小鼠中更有效，并且再次提供的保护是NK细胞介导的并且不依赖于IL-17 A。进一步的研究表明，IL-23的缺失促进了所检查的两种转移模型中的穿孔素和IFN-γ抗肿瘤效应子功能。在两种不同的小鼠致癌模型中，IL-23缺乏也显著地保护小鼠免于肿瘤形成，其中对宿主IL-12 p40和IL-17 A的依赖性是完全不同的。值得注意的是，在3 '-甲基胆蒽（MCA）诱导的纤维肉瘤模型中，这种保护在不存在NK细胞的情况下完全丧失。总体而言，这些数据表明IL-23在抑制天然或精氨酸诱导的先天免疫、促进肿瘤发展和转移中发挥的一般作用，与IL-17 A无关。
IL-23 is an important molecular driver of Th17 cells and has strong tumor-promoting proinflammatory activity postulated to occur via adaptive immunity. Conversely, more recently it has been reported that IL-17A elicits a protective inflammation that promotes the activation of tumor-specific CD8(+) T cells. Here we show the much broader impact of IL-23 in antagonizing antitumor immune responses primarily mediated by innate immunity. Furthermore, the majority of this impact was independent of IL-17A, which did not appear critical for many host responses to tumor initiation or metastases. IL-23-deficient mice were resistant to experimental tumor metastases in three models where host NK cells controlled disease. Immunotherapy with IL-2 was more effective in mice lacking IL-23, and again the protection afforded was NK cell mediated and independent of IL-17A. Further investigation revealed that loss of IL-23 promoted perforin and IFN-gamma antitumor effector function in both metastasis models examined. IL-23-deficiency also strikingly protected mice from tumor formation in two distinct mouse models of carcinogenesis where the dependence on host IL-12p40 and IL-17A was quite different. Notably, in the 3'-methylcholanthrene (MCA) induction of fibrosarcoma model, this protection was completely lost in the absence of NK cells. Overall, these data indicate the general role that IL-23 plays in suppressing natural or cytokine-induced innate immunity, promoting tumor development and metastases independently of IL-17A.