Nrf2 Induces IL-17D to Mediate Tumor and Virus Surveillance.
Nrf2 Induces IL-17D to Mediate Tumor and Virus Surveillance.
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DOI：
10.1016/j.celrep.2016.07.075
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发表时间：
2016-08-30
期刊：
影响因子：
8.8
通讯作者：
Bui JD
中科院分区：
文献类型：
--
作者：
Saddawi-Konefka R;Seelige R;Gross ET;Levy E;Searles SC;Washington A Jr;Santosa EK;Liu B;O'Sullivan TE;Harismendy O;Bui JD
处于异种或氧化应激状态的细胞激活转录因子Nrf2，启动一种内在的“应激监视”途径。我们最近发现，细胞因子IL-17D通过诱导抗肿瘤免疫来影响一种外部应激监视，但IL-17D是如何调节的仍不清楚。在这里，我们展示了Nrf2诱导癌细胞系中IL-17D的作用。此外，Nrf2和IL-17D在原发肿瘤和体内病毒感染过程中均有表达。IL-17D在肿瘤和病毒感染细胞中的表达对于最佳宿主保护至关重要，因为与WT动物相比，IL17d−/−小鼠经历了更高的肿瘤发病率和加重的病毒感染。此外，在已建立的肿瘤中，激活Nrf2诱导IL-17D导致自然杀伤细胞依赖的肿瘤消退。这些数据表明，Nrf2可以启动内在和外在的应激监测途径，并强调了Nrf2激动剂作为癌症和感染的免疫疗法的使用。萨达维-科内夫卡等人。证明转录因子核因子红系衍生2，或NRF2，诱导细胞因子白介素17D。NRF2/IL-17D介导的自然杀伤细胞募集可以导致已建立的肿瘤的消退。因此，使用NRF2激动剂诱导IL-17D有可能用于肿瘤免疫治疗。
Cells undergoing xenobiotic or oxidative stress activate the transcription factor Nrf2, which initiates an intrinsic “stress surveillance” pathway. We recently found that the cytokine IL-17D effects a form of extrinsic stress surveillance by inducing antitumor immunity, but how IL-17D is regulated remains unknown. Here, we show that Nrf2 induced IL-17D in cancer cell lines. Moreover, both Nrf2 and IL-17D were induced in primary tumors as well as during viral infection in vivo. Expression of IL-17D in tumors and virally infected cells is essential for optimal protection of the host as il17d−/− mice experienced a higher incidence of tumors and exacerbated viral infections compared to WT animals. Moreover, activating Nrf2 to induce IL-17D in established tumors led to natural killer cell-dependent tumor regression. These data demonstrate that Nrf2 can initiate both intrinsic and extrinsic stress surveillance pathways and highlight the use of Nrf2 agonists as immune therapies for cancer and infection. Saddawi-Konefka et al. show that the transcription factor nuclear factor erythroid derived 2- like 2, or Nrf2, induces the cytokine interleukin-17D. Nrf2/IL-17D-mediated natural killer cell recruitment can lead to the regression of established tumors. Therefore, inducing IL-17D using Nrf2 agonists has potential for cancer immune therapy.
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