C/EBPδ and STAT-1 Are Required for TLR8 Transcriptional Activity
C/EBPδ and STAT-1 Are Required for TLR8 Transcriptional Activity
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DOI：
10.1074/jbc.m110.133884
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发表时间：
2010-11-05
影响因子：
4.8
通讯作者：
Hasan, Uzma A.
中科院分区：
文献类型：
--
作者：
Zannetti, Claudia;Bonnay, Francois;Hasan, Uzma A.
Toll样受体8（TLR 8）主要在骨髓细胞中表达，在启动对病毒单链RNA的免疫应答中起着核心作用。尽管在TLR 8研究领域有很大的兴趣，但在TLR 8生物学及其转录调控方面知之甚少。在这里，我们描述的hTLR 8启动子的分离和参与其调节的分子机制的表征。报告基因分析和ChIP分析表明，hTLR 8的基础转录调控是通过三个C/EBP顺式作用元件，需要C/EBP δ和C/EBP β活性。此外，我们观察到，R848刺激通过增强C/EBP δ而不是C/EBP β与TLR 8启动子内其应答位点的结合来增加TLR 8转录活性。此外，我们发现IFN-γ还通过STAT 1转录因子与TLR 8启动子上的IFN-γ激活序列元件的结合来增加TLR 8转录活性，并增强TLR 8功能。这些结果揭示了TLR 8介导的先天免疫应答的机制。
Toll-like receptor 8 (TLR8), which is expressed primarily in myeloid cells, plays a central role in initiating immune responses to viral single-stranded RNA. Despite the great interest in the field of TLR8 research, very little is known in terms of TLR8 biology and its transcriptional regulation. Here, we describe the isolation of the hTLR8 promoter and the characterization of the molecular mechanisms involved in its regulation. Reporter gene analysis and ChIP assays demonstrated that the hTLR8 regulation of the basal transcription is regulated via three C/EBP cis-acting elements that required C/EBP delta and C/EBP beta activity. In addition, we observed that R848 stimulation increases TLR8 transcriptional activity via an enhanced binding of C/EBP delta, and not C/EBP beta, to its responsive sites within the TLR8 promoter. Moreover, we showed that IFN-gamma also increased TLR8 transcription activity via the binding of STAT1 transcription factor to IFN-gamma activated sequence elements on the TLR8 promoter and enhanced TLR8 functionality. These results shed new light on the mechanisms involved during TLR8-mediated innate immune response.