HSV-2 Infection of Human Genital Epithelial Cells Upregulates TLR9 Expression Through the SP1/JNK Signaling Pathway
HSV-2 Infection of Human Genital Epithelial Cells Upregulates TLR9 Expression Through the SP1/JNK Signaling Pathway
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人生殖器上皮细胞的 HSV-2 感染通过 SP1/JNK 信号通路上调 TLR9 表达。
DOI：
10.3389/fimmu.2020.00356
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发表时间：
2020-03-04
影响因子：
7.3
通讯作者：
Hu, Qinxue
中科院分区：
文献类型：
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作者：
Hu, Kai;Fu, Ming;Hu, Qinxue
众所周知，单纯疱疹病毒2型（HSV-2）触发toll样受体（TLR） 9信号通路的激活，从而在树突状细胞中产生抗病毒细胞因子。然而，HSV-2感染对HSV-2主要靶点生殖器上皮细胞TLR9表达和信号传导的影响尚未确定。本研究以人生殖上皮细胞系和原代生殖上皮细胞为模型，发现HSV-2感染可在mRNA和蛋白水平上增强TLR9的表达。这种增强依赖于病毒复制且不依赖于cpg，而hsv -2介导的TLR9上调并不激活TLR9信号通路。从机制上讲，TLR9启动子上的SP1结合位点似乎对hsv -2诱导的TLR9转录激活至关重要。2型单纯疱疹病毒感染后，SP1从细胞质转移到细胞核，并与TLR9启动子结合。通过使用特异性抑制剂，JNK信号通路参与HSV-2诱导的TLR9转激活，而HSV-2感染增加了JNK的磷酸化，但不增加总水平。与此一致，JNK信号通路的拮抗抑制hsv -2诱导的SP1核易位。综上所述，我们的研究表明HSV-2感染人类生殖器上皮细胞通过SP1/JNK信号通路促进TLR9的表达。本研究的发现为hsv -2-宿主相互作用和免疫干预的潜在靶点提供了见解。
It is known that herpes simplex virus type 2 (HSV-2) triggers the activation of Toll-like receptor (TLR) 9 signaling pathway and the consequent production of antiviral cytokines in dendritic cells. However, the impact of HSV-2 infection on TLR9 expression and signaling in genital epithelial cells, the primary HSV-2 targets, has yet to be determined. In the current study, by using both human genital epithelial cell lines and primary genital epithelial cells as models, we found that HSV-2 infection enhances TLR9 expression at both mRNA and protein levels. Such enhancement is virus replication-dependent and CpG-independent, while the HSV-2-mediated upregulation of TLR9 does not activate TLR9 signaling pathway. Mechanistically, a SP1 binding site on TLR9 promoter appears to be essential for HSV-2-induced TLR9 transactivation. Upon HSV-2 infection, SP1 translocates from the cytoplasm to the nucleus, and consequently binds to TLR9 promoter. By using specific inhibitors, the JNK signaling pathway is shown to be involved in the HSV-2-induced TLR9 transactivation, while HSV-2 infection increases the phosphorylation but not the total level of JNK. In agreement, antagonism of JNK signaling pathway inhibits the HSV-2-induced SP1 nuclear translocation. Taken together, our study demonstrates that HSV-2 infection of human genital epithelial cells promotes TLR9 expression through SP1/JNK signaling pathway. Findings in this study provide insights into HSV-2-host interactions and potential targets for immune intervention.