Transcriptional Repression of IFN Regulatory Factor 7 by MYC Is Critical for Type I IFN Production in Human Plasmacytoid Dendritic Cells.
Transcriptional Repression of IFN Regulatory Factor 7 by MYC Is Critical for Type I IFN Production in Human Plasmacytoid Dendritic Cells.
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DOI：
10.4049/jimmunol.1502385
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发表时间：
2016-10-15
期刊：
影响因子：
--
通讯作者：
Liu YJ
中科院分区：
文献类型：
--
作者：
Kim TW;Hong S;Lin Y;Murat E;Joo H;Kim T;Pascual V;Liu YJ
I型干扰素（IFN）是人类先天性和适应性免疫的重要介质，并且由浆细胞样树突状细胞（pDC）大量产生。当病原体通过pDC中的Toll样受体（TLR）7/9检测时，IRF 7是I型IFN产生的关键调节剂。然而，pDC的过度活化可导致危及生命的自身免疫性疾病。为了避免异常pDC活化的有害作用，需要对IRF 7进行严格调节。尽管如此，IRF 7转录如何在pDC中调节的详细机制仍然难以捉摸。MYC是一种高度多效性的转录因子，但其在pDC功能中的作用还不清楚。为了鉴定转录因子MYC在人pDC中的作用，我们采用了使用人pDC细胞系GEN2.2的敲低技术。当我们敲低pDC细胞系中的MYC时，IFN刺激的基因的产生显著增加，并且通过TLR 9激动剂CpGB进一步增强。有趣的是，MYC显示通过与NCOR 2/HDAC 3相互作用而被募集到IRF 7启动子区域以进行其抑制。此外，TLR 9介导的NF-κ B和MAPK的激活以及IRF 7的核转位通过MYC去除而大大增强。MYC的药物抑制恢复了IRF 7表达，进一步证实了MYC在pDC的抗病毒应答中的负面作用。因此，我们的研究结果确定了MYC在人pDC中的新的免疫调节作用，并可能增加我们对癌症和自身免疫性疾病中异常pDC功能的理解。
Type I interferons (IFN) are crucial mediators of human innate and adaptive immunity and are massively produced from plasmacytoid dendritic cells (pDC). IRF7 is a critical regulator of type I IFN production when pathogens are detected by Toll-like receptor (TLR) 7/9 in pDC. However, hyperactivation of pDC can cause life-threatening autoimmune diseases. To avoid the deleterious effects of aberrant pDC activation, tight regulation of IRF7 is required. Nonetheless, the detailed mechanisms of how IRF7 transcription is regulated in pDC are still elusive. MYC is a well-known highly pleiotropic transcription factor however the role of MYC in pDC function is not well defined yet. To identify the role of transcription factor MYC in human pDC, we employed a knockdown technique using human pDC cell line, GEN2.2. When we knocked down MYC in the pDC cell line, production of IFN-stimulated genes was dramatically increased and was further enhanced by the TLR9 agonist CpGB. Interestingly, MYC is shown to be recruited to the IRF7 promoter region through interaction with NCOR2/HDAC3 for its repression. In addition, activation of TLR9-mediated NF-kB and MAPK and nuclear translocation of IRF7 were greatly enhanced by MYC depletion. Pharmaceutical inhibition of MYC recovered IRF7 expression, further confirming the negative role of MYC in the antiviral response by pDC. Therefore, our results identify the novel immunomodulatory role of MYC in human pDC and may add to our understanding of aberrant pDC function in cancer and autoimmune disease.
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