Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription.
Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription.
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Nrf2通过阻断促炎细胞因子转录抑制巨噬细胞炎症反应。
DOI：
10.1038/ncomms11624
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发表时间：
2016-05-23
影响因子：
16.6
通讯作者：
Yamamoto M
中科院分区：
文献类型：
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作者：
Kobayashi EH;Suzuki T;Funayama R;Nagashima T;Hayashi M;Sekine H;Tanaka N;Moriguchi T;Motohashi H;Nakayama K;Yamamoto M
Nrf2 （nf - e2相关因子-2）转录因子调节氧化/异种应激反应并抑制炎症。然而，Nrf2减轻炎症的机制尚不清楚。在这里，我们证明Nrf2干扰脂多糖诱导的促炎细胞因子的转录上调，包括IL-6和IL-1β。染色质免疫沉淀(ChIP)-seq和ChIP- qpcr分析显示，Nrf2在巨噬细胞中与这些基因附近结合，抑制RNA Pol II的募集。此外，我们发现nrf2介导的抑制与nrf2结合基序和活性氧水平无关。小鼠炎症模型进一步证明，Nrf2在体内干扰il - 6诱导和炎症表型。因此，与广泛接受的Nrf2通过氧化还原控制抑制炎症的观点相反，我们在这里证明Nrf2反对促炎细胞因子基因的转录上调。本研究确定Nrf2是细胞因子产生的上游调节因子，并为Nrf2介导的抗炎症途径建立了分子基础。Nrf2是氧化应激反应基因的转录激活因子。在这里，作者表明Nrf2与促炎基因的启动子结合，并在lps刺激的巨噬细胞中干扰其转录上调，而不依赖于其在活性氧调节中的作用。
Nrf2 (NF-E2-related factor-2) transcription factor regulates oxidative/xenobiotic stress response and also represses inflammation. However, the mechanisms how Nrf2 alleviates inflammation are still unclear. Here, we demonstrate that Nrf2 interferes with lipopolysaccharide-induced transcriptional upregulation of proinflammatory cytokines, including IL-6 and IL-1β. Chromatin immunoprecipitation (ChIP)-seq and ChIP-qPCR analyses revealed that Nrf2 binds to the proximity of these genes in macrophages and inhibits RNA Pol II recruitment. Further, we found that Nrf2-mediated inhibition is independent of the Nrf2-binding motif and reactive oxygen species level. Murine inflammatory models further demonstrated that Nrf2 interferes with IL6 induction and inflammatory phenotypes in vivo. Thus, contrary to the widely accepted view that Nrf2 suppresses inflammation through redox control, we demonstrate here that Nrf2 opposes transcriptional upregulation of proinflammatory cytokine genes. This study identifies Nrf2 as the upstream regulator of cytokine production and establishes a molecular basis for an Nrf2-mediated anti-inflammation approach. Nrf2 is a transcriptional activator of oxidative stress response genes. Here the authors show that Nrf2 binds to promoters of proinflammatory genes and interferes with their transcriptional upregulation in LPS-stimulated macrophages independently of its role in regulation of reactive oxygen species.