Department of Immunology, Moffitt Cancer Center, University of South Florida, Tampa, FL 33612, USA.
J Immunol. 2010 Aug 1;185(3):1720-9. doi: 10.4049/jimmunol.1000114. Epub 2010 Jul 7.
RNA virus infection results in expression of type 1 IFNs, especially IFN-alpha/beta, which play a crucial role in host antivirus responses. Type 1 IFNs are induced in a cell type-specific manner through TLR and RIG-I-like receptor pathways, both of which activate IFN regulatory factors (IRFs) and NF-kappaB transcription factors. Although NF-kappaB activation and association with the IFN-beta promoter after RNA virus infection is well documented, our previous work showed that, surprisingly, NF-kappaB is not essential for IFN-beta gene expression. Thus, the actual function of NF-kappaB in IFN-beta expression and virus replication is not clear. In this study, we found Newcastle disease virus and vesicular stomatitis virus replication is enhanced in mouse embryonic fibroblasts (MEFs) lacking the NF-kappaB RelA subunit. Increased virus replication was traced to a specific requirement for RelA in early virus-induced IFN-beta expression. At these time points, when IFN-beta expression is ~100-fold less than peak levels, impaired IFN-beta production delayed IFN-induced gene expression, resulting in increased virus replication in RelA(-/-) MEFs. Importantly, our results show that RelA requirement is crucial only when IRF3 activation is low. Thus, high levels of activated IRF3 expression are sufficient for induction of IFN-beta in RelA(-/-) MEFs, transcriptional synergism with the coactivator CREB-binding protein, and rescue of susceptibility to virus. Together, these findings indicate that NF-kappaB RelA is not crucial for regulating overall IFN-beta production, as previously believed; instead, RelA is specifically required only during a key early phase after virus infection, which substantially impacts the host response to virus infection.
RNA 病毒感染导致 1 型干扰素（IFN）的表达，特别是 IFN-α/β，它们在宿主抗病毒反应中起着至关重要的作用。1 型 IFN 以细胞类型特异性的方式通过 TLR 和 RIG-I 样受体途径诱导，这两种途径都激活 IFN 调节因子（IRFs）和 NF-κB 转录因子。尽管 RNA 病毒感染后 NF-κB 的激活及其与 IFN-β启动子的结合已得到充分证实，但我们之前的工作表明，令人惊讶的是，NF-κB 对于 IFN-β基因表达并非必不可少。因此，NF-κB 在 IFN-β表达和病毒复制中的实际功能尚不清楚。在这项研究中，我们发现缺乏 NF-κB RelA 亚基的小鼠胚胎成纤维细胞（MEFs）中，新城疫病毒和水疱性口炎病毒的复制增强。病毒复制的增加可归因于 RelA 在早期病毒诱导的 IFN-β表达中具有特异性要求。在这些时间点，当 IFN-β表达水平比峰值低约 100 倍时，IFN-β产生受损会延迟 IFN 诱导基因表达，从而导致 RelA（-/-）MEFs 中的病毒复制增加。重要的是，我们的结果表明，只有在 IRF3 激活水平较低时，RelA 的要求才至关重要。因此，高水平激活的 IRF3 表达足以在 RelA（-/-）MEFs 中诱导 IFN-β，与共激活子 CREB 结合蛋白的转录协同作用，并挽救对病毒的易感性。总之，这些发现表明，NF-κB RelA 对于调节 IFN-β的整体产生并不像以前认为的那样至关重要；相反，RelA 仅在病毒感染后的关键早期阶段才需要特异性表达，这会极大地影响宿主对病毒感染的反应。
