TLR3在HSV-1感染小鼠NSCs中的作用研究
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摘要
目的：
1.探讨TLR3在HSV-1感染小鼠NSCs中的作用,研究HSV-1通过TLR3对NF-κB转录活性及细胞因子TNF-α和IL-10表达的影响。
2.研究TLR3在HSV-1感染小鼠NSCs中对IRF3磷酸化及IFN-β表达的影响。
材料和方法：
1.体外分离并用含mEGF、mbFGF和B27的NSCs生长培养基培养小鼠胚胎皮层NSCs,通过免疫荧光方法检测NSCs标志物的表达并对NSCs分化能力进行鉴定。
2. HSV-1感染原代培养的第3代NSCs,通过免疫荧光、RT-PCR、Western blot、 ELISA等方法分别检测TLR3、NF-κB、TNF-α、IL-10mRNA和蛋白的表达,同时研究NF-κB通路抑制剂PDTC及TLR3中和抗体对NF-κB通路的影响。
3. HSV-1感染原代培养的第3代NSCs,并构建沉默TLR3(?)勺慢病毒载体感染NSCs,抑制TLR3的表达,通过免疫荧光、RT-PCR、Western blot、ELISA等方法研究NSCs中TLR3和IRF3及IFN-β的表达特点。
结果：
1.正常状态下,NSCs表达TLR3和NF-κB:被HSV-1感染的NSCs,核内NF-κB蛋白表达明显增强,同时炎性细胞因子TNF-α、IL-10在mRNA和蛋白水平的表达均上调。PDTC (?)丁抑制NF-B活化,使核内NF-κB蛋白表达下调,导致细胞内TNF-α、IL-10mRNA和蛋白的表达下调。用TLR3中和抗体阻断NSCs表面TLR3后,核内NF-κB蛋白表达下调,INF-α、IL-10mRNA和蛋白也明显下调,NSCs通过天然免疫抗病毒作用减弱,表现为HSV-1gD mRNA在细胞内表达明显增强,病毒滴度增高。
2. NSCs被HSV-1感染后,IRF3mRNA表达上调,其蛋白磷酸化也明显增强,同时IFN-β mRNA和蛋白的表达也相应上调。用慢病毒抑制TLR3表达后,IRF3mRNA及其蛋白磷酸化明显下调,同时IFN-β mRNA和蛋白的表达也相应下调,并且HSV-1在细胞内复制增加,病毒滴度增高。
结论：
1. NSCs是HSV-1的完全容许细胞。正常NSCs表达TLR3、NF-κB;被HSV-1感染的NSCs通过TLR3活化NF-κB,从而上调炎性细胞因子TNF-α、IL-10的表达,发挥天然免疫抗病毒作用。
2. HSV-1感染NSCs后,TLR3表达上调,促进IRF3磷酸化后核转位,从而上调IFN-β的表达,激活细胞天然免疫,抵抗HSV-1感染。
Objective:
1. To investigate the effect of HSV-1infection on mouse neural stem cells (NSCs) and to study the effects of HSV-1via TLR3on nuclear factor-kappaB (NF-κB) transcriptional activity and tumor necrosis factor-alpha (TNF-α) and interleukin-10(IL-10) expression.
2. To investigate the effect of Herpes simplex virus1(HSV-1) via TLR3on NSCs and HSV-1infection on phosphorylation of Interferon regulatory factor3(IRF3) and expression of interferon-β (IFN-β).
Materials and methods:
1. Mouse NSCs from cerebral cortex was isolated in vitro and cultured with mEGF, mbFGF and B27. Immunofluorescent staining was used to detect the NSCs marker and differentiation.
2. Primarily cultured third-passage NSCs were infected by HSV-1. Immunofluorescent staining,reverse transcript PCR (RT-PCR),Western blot and ELISA were used to detect mRNA and protein expression of TLR3, NF-κB, TNF-α and IL-10. In addition, the effects of NF-κB pathway inhibitor PDTC and TLR3-specific antibody on NF-κB pathway.
3. Primarily cultured third-passage NSCs were infected by HSV-1. Lentivirus mediated RNAi plasmid was constructed to produce lentivirus and to transduct NSCs. Immunofluorescent staining. RT-PCR.Western blot and ELISA were used to detect expression of TLR3, IRF3and IFN-β expression.
Results:
1. Under uninfected conditions, NSCs expressed TLR3and NF-κB at the mRNA and protein levels. When infected by HSV-1,nuclear protein of NF-κB was significantly expressed significantly. Meanwhile, the mRNA and protein levels of TNF-α and IL-10were all up-regulated. PDTC inhibited NF-κB activation and resulted in down-regulation of nuclear NF-κB protein, which led to down-regulation of TNF-α and IL-10mRNAs and proteins. After blocking NSC membrane TLR3with neutralizing antibody, the nuclear NF-κB protein expression was down-regulated and TNF-α and IL-10mRNAs and proteins were down-regulated significantly. The antiviral functions of NSCs were weaker, as indicated by higher HSV-1gD mRNA expression and increased HSV-1virus titers.
2. After infection with HSV-1, The IRF3mRNA up-regulated expressed with significant protein phosphorylation. Meanwhile, the mRNA and protein levels of IFN-β were up-regulated. When using a lentivirus-mediated system silencing TLR3gene in NSCs, IRF3mRNA and protein phosphorylation were clearly down-regulated, as well as IFN-β mRNA and protein down-regulation accordingly. Furthermore, the HSV-1multiplications in NSCs increased with strengthen virus titers.
Conclusion:
1. The NSCs were fully permissive for the HSV-1. The uninfected NSCs expressed TLR3and NF-κB at the mRNA and protein levels. Infected NSCs play antiviral role via activating NF-κB so as to up-regulate TNF-α and IL-10expression.
2. After infection with HSV-1, TLR3mRNA and protein levels of NSCs were up-regulated to promote IRF3phosphorylation and nucleus translocation so as to up-regulate IFN-β expression to play antiviral function via cells Innate immune.
1.探讨TLR3在HSV-1感染小鼠NSCs中的作用,研究HSV-1通过TLR3对NF-κB转录活性及细胞因子TNF-α和IL-10表达的影响。
2.研究TLR3在HSV-1感染小鼠NSCs中对IRF3磷酸化及IFN-β表达的影响。
材料和方法：
1.体外分离并用含mEGF、mbFGF和B27的NSCs生长培养基培养小鼠胚胎皮层NSCs,通过免疫荧光方法检测NSCs标志物的表达并对NSCs分化能力进行鉴定。
2. HSV-1感染原代培养的第3代NSCs,通过免疫荧光、RT-PCR、Western blot、 ELISA等方法分别检测TLR3、NF-κB、TNF-α、IL-10mRNA和蛋白的表达,同时研究NF-κB通路抑制剂PDTC及TLR3中和抗体对NF-κB通路的影响。
3. HSV-1感染原代培养的第3代NSCs,并构建沉默TLR3(?)勺慢病毒载体感染NSCs,抑制TLR3的表达,通过免疫荧光、RT-PCR、Western blot、ELISA等方法研究NSCs中TLR3和IRF3及IFN-β的表达特点。
结果：
1.正常状态下,NSCs表达TLR3和NF-κB:被HSV-1感染的NSCs,核内NF-κB蛋白表达明显增强,同时炎性细胞因子TNF-α、IL-10在mRNA和蛋白水平的表达均上调。PDTC (?)丁抑制NF-B活化,使核内NF-κB蛋白表达下调,导致细胞内TNF-α、IL-10mRNA和蛋白的表达下调。用TLR3中和抗体阻断NSCs表面TLR3后,核内NF-κB蛋白表达下调,INF-α、IL-10mRNA和蛋白也明显下调,NSCs通过天然免疫抗病毒作用减弱,表现为HSV-1gD mRNA在细胞内表达明显增强,病毒滴度增高。
2. NSCs被HSV-1感染后,IRF3mRNA表达上调,其蛋白磷酸化也明显增强,同时IFN-β mRNA和蛋白的表达也相应上调。用慢病毒抑制TLR3表达后,IRF3mRNA及其蛋白磷酸化明显下调,同时IFN-β mRNA和蛋白的表达也相应下调,并且HSV-1在细胞内复制增加,病毒滴度增高。
结论：
1. NSCs是HSV-1的完全容许细胞。正常NSCs表达TLR3、NF-κB;被HSV-1感染的NSCs通过TLR3活化NF-κB,从而上调炎性细胞因子TNF-α、IL-10的表达,发挥天然免疫抗病毒作用。
2. HSV-1感染NSCs后,TLR3表达上调,促进IRF3磷酸化后核转位,从而上调IFN-β的表达,激活细胞天然免疫,抵抗HSV-1感染。
Objective:
1. To investigate the effect of HSV-1infection on mouse neural stem cells (NSCs) and to study the effects of HSV-1via TLR3on nuclear factor-kappaB (NF-κB) transcriptional activity and tumor necrosis factor-alpha (TNF-α) and interleukin-10(IL-10) expression.
2. To investigate the effect of Herpes simplex virus1(HSV-1) via TLR3on NSCs and HSV-1infection on phosphorylation of Interferon regulatory factor3(IRF3) and expression of interferon-β (IFN-β).
Materials and methods:
1. Mouse NSCs from cerebral cortex was isolated in vitro and cultured with mEGF, mbFGF and B27. Immunofluorescent staining was used to detect the NSCs marker and differentiation.
2. Primarily cultured third-passage NSCs were infected by HSV-1. Immunofluorescent staining,reverse transcript PCR (RT-PCR),Western blot and ELISA were used to detect mRNA and protein expression of TLR3, NF-κB, TNF-α and IL-10. In addition, the effects of NF-κB pathway inhibitor PDTC and TLR3-specific antibody on NF-κB pathway.
3. Primarily cultured third-passage NSCs were infected by HSV-1. Lentivirus mediated RNAi plasmid was constructed to produce lentivirus and to transduct NSCs. Immunofluorescent staining. RT-PCR.Western blot and ELISA were used to detect expression of TLR3, IRF3and IFN-β expression.
Results:
1. Under uninfected conditions, NSCs expressed TLR3and NF-κB at the mRNA and protein levels. When infected by HSV-1,nuclear protein of NF-κB was significantly expressed significantly. Meanwhile, the mRNA and protein levels of TNF-α and IL-10were all up-regulated. PDTC inhibited NF-κB activation and resulted in down-regulation of nuclear NF-κB protein, which led to down-regulation of TNF-α and IL-10mRNAs and proteins. After blocking NSC membrane TLR3with neutralizing antibody, the nuclear NF-κB protein expression was down-regulated and TNF-α and IL-10mRNAs and proteins were down-regulated significantly. The antiviral functions of NSCs were weaker, as indicated by higher HSV-1gD mRNA expression and increased HSV-1virus titers.
2. After infection with HSV-1, The IRF3mRNA up-regulated expressed with significant protein phosphorylation. Meanwhile, the mRNA and protein levels of IFN-β were up-regulated. When using a lentivirus-mediated system silencing TLR3gene in NSCs, IRF3mRNA and protein phosphorylation were clearly down-regulated, as well as IFN-β mRNA and protein down-regulation accordingly. Furthermore, the HSV-1multiplications in NSCs increased with strengthen virus titers.
Conclusion:
1. The NSCs were fully permissive for the HSV-1. The uninfected NSCs expressed TLR3and NF-κB at the mRNA and protein levels. Infected NSCs play antiviral role via activating NF-κB so as to up-regulate TNF-α and IL-10expression.
2. After infection with HSV-1, TLR3mRNA and protein levels of NSCs were up-regulated to promote IRF3phosphorylation and nucleus translocation so as to up-regulate IFN-β expression to play antiviral function via cells Innate immune.
引文
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