卡波氏肉瘤相关疱疹病毒(KSHV)vIL-6通过IRF-3负性调控IFN-β转录表达

Interleukin-6 from Kaposi's Sarcoma-associated Herpesvirus Negatively Regulates Expression of Interferon-β through Interferon Regulatory Factor-3

卡波氏肉瘤相关疱疹病毒(Kaposi's sarcoma-associated herpesvirus,KSHV),又称人类疱疹病毒8型(Human herpesvirus 8,HHV-8),是艾滋病感染者中发病率最高的肿瘤-卡波氏肉瘤的致病性病原体。本实验对KSHV裂解期蛋白-病毒白细胞介素6(Viral interleukin-6,vIL-6)抑制宿主固有免疫机制进行初步探讨。利用仙台病毒刺激人胚肾细胞(HEK293T)激活抗病毒固有免疫,观察vIL-6过表达后对IFN-β的作用及机制,利用实时定量PCR检测IFN-β基因表达及双荧光素酶实验分析IFN-β基因启动子的活性。过表达vIL-6后,IFN-β基因mRNA水平表达明显下降,进一步实验证明vIL-6可抑制IFN-β基因启动子活性,且vIL-6可特异性作用于IFN-β基因启动子PRDIII-PRDI区。本研究首次证实了KSHV vIL-6可通过抑制IFN-β启动子活性从而调控IFN-β表达,且这种作用主要通过IRF-3信号途径。

Kaposi＇s sarcoma-associated herpesvirus（KSHV）,also known as human herpesvirus-8,is linked etiologically to the development of Kaposi＇s sarcoma,the most commonly found cancer in patients with the acquired immunodeficiency disease syndrome.We investigated the mechanism of viral interleukin-6（vIL-6）-based inhibition of the innate immune response.Transfection of the sendai virus to HEK293 Tcells was done to initiate the innate immune.The effect of vIL-6from KSHV on interferon（IFN）-βand the mechanism of action was explored.Real-time quantitative polymerase chain reaction and luciferase assays were used to evaluate relative gene expression or promoter activity after vIL-6overexpression.Results showed that vIL-6depressed expression of the IFN-βgene at the mRNA level.The promoter activity of the IFN-βgene was reduced dramatically upon co-transfection with the vIL-6plasmid.vIL-6affected only the PRDIII-PRDI region in the IFN-βgene promoter,which can bind interferon regulatory factor-3（IRF-3）to regulate gene expression.We discovered that one of the mechanisms of vIL-6immunosuppression was that vIL-6could inhibit IFN-βexpression through reduction of the activity of the IFN-βgene promoter,and that this effect was dependent on the IRF-3signaling pathway.