IL-10、IL-4及其信号通路在HSV-1激活KSHV复制中的作用
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摘要
卡波济肉瘤相关疱疹病毒(Kaposi's sarcoma-associatedherpesvirus,KSHV)感染是卡波济肉瘤(Kaposi's sarcoma,KS)发生的必要条件,但如果没有其它协同因子的作用也不足以引发KS,然而促使KSHV引发KS的因素还未完全清楚。课题组先前的研究发现,人类疱疹病毒6型(human herpesvirus 6,HHV-6)和人类免疫缺陷病毒1型(human immunodelficiency virus type 1,HIV-1)反式激活蛋白(transactivative transcription protein,Tat)是激活KSHV裂解性周期复制的重要协同因子,本研究中我们进一步探讨了人类单纯疱疹病毒1型(human herpes simplex virus-1,HSV-1)影响KSHV复制的潜能。本文通过检测原发性渗出性淋巴瘤【primary effusionlymphoma,PEL,又称体腔渗出性淋巴瘤(body cavity-basedlymphoma,BCBL)】来源的BCBL-1细胞中KSHV裂解期基因mRNA转录、裂解期蛋白表达和感染性病毒颗粒释放,证实HSV-1是KS致病过程中的一个潜在的重要因素。检测KSHV ORF50启动子驱动活性的虫荧光素酶报告实验并配合针对ORF50的小干扰RNA(smallinterference RNA,siRNA)技术进一步确实了上述结果,表明HSV-1通过直接激活ORF50表达来诱导KSHV复制。机制方面的研究证实,HSV-1可以诱导人白细胞介素(interleukin,IL)-10及其受体(IL-10receptor alpha,IL-10Rα)、IL-4及其受体(IL-4 receptor,IL-4R)的表达;以中和抗体封闭IL-10或IL-4能够抑制HSV-1诱导的KSHV复制。另外,IL-10/IL-10Rα、IL-4/IL-4R能够激活PI3K/AKT、ERKMAPK和JAK2信号通路【PI3K:磷脂酰肌醇3激酶(phosphatidylinositol 3-kinase,PI3K);AKT:又称蛋白激酶B(proteinkinase B,PKB);MAPK:丝裂原活化蛋白激酶(mitogen-activatedprotein kinase,MAPK);ERK:细胞外信号调节蛋白激酶(extracellularsignal-regulated protein kinases,ERK);JAK2:Janus激酶(Janus kinase,JAK)2】。PI3K抑制剂LY294002、ERK抑制剂peptideⅡ和JAK2抑制剂AG490均可以降低HSV-1诱导的KSHV复制。上述研究结果表明,HSV-1可能通过诱导KSHV复制提高病毒载量从而参与KS的发病;IL-10、IL-4及其信号通路在调控HSV-1诱导KSHV复制的过程中发挥重要作用。本研究结果提示,阻断PI3K/AKT、ERK MAPK和JAK2信号通路对KS患者的治疗有一定意义。
Kaposi's sarcoma-associated herpesvirus (KSHV) infection appears to be necessary but not sufficient for Kaposi's sarcoma (KS) development without other cofactors. However, factors that facilitate KSHV to cause KS have not been well defined. Previously, we identified that both human herpesvirus 6 (HHV-6) and human immunodeficiency virus type 1 (HIV-1) Tat were important cofactors that activated lytic cycle replication of KSHV. Here, we further investigated the potential of human herpes simplex virus-1 (HSV-1) to influence KSHV replication. We demonstrated that HSV-1 was a potentially important factor in the pathogenesis of KS, as determined by production of lytic phase mRNA transcripts, viral proteins and infectious viral particls in BCBL-1 cells. These results were further confirmed by a luciferase reporter assay testing ORF50 promoter-driven luciferase activity and an RNA interference experiment using small interfering RNA (siRNA) targeting KSHV ORF50. Studies on mechanism showed that HSV-1 induced the production of interleukin-10 (IL-10) and its receptor (IL-10Rα), interleukin-4 (IL-4) and its receptor (IL-4R). Neutralization of IL-10 or IL-4 with corresponding neutralizing antibodies decreased the lytic cycle replication of KSHV by HSV-1. In addition, IL-10/IL-10Ra and IL-4/IL-4R from HSV-1-infected BCBL-1 cells activated PI3K/AKT, ERK MAPK and JAK2 signalings. Addition of LY294002, PI3K inhibitor, peptide II, ERK inhibitor and AG490, JAK2 inhibitor into cell culture significantly decreased the lytic replication of KSHV by HSV-1. These findings suggest that HSV-1 may participate in KS pathogenesis by inducing KSHV replication and increasing KSHV viral load. IL-10、IL-4 and their signalings played an important role in modulation of HSV-1-induced KSHV replication. These data also suggest that the blockage of PI3K/AKT, ERK MAPK and JAK2 signalings may be of therapeutic value in KS patients.
Kaposi's sarcoma-associated herpesvirus (KSHV) infection appears to be necessary but not sufficient for Kaposi's sarcoma (KS) development without other cofactors. However, factors that facilitate KSHV to cause KS have not been well defined. Previously, we identified that both human herpesvirus 6 (HHV-6) and human immunodeficiency virus type 1 (HIV-1) Tat were important cofactors that activated lytic cycle replication of KSHV. Here, we further investigated the potential of human herpes simplex virus-1 (HSV-1) to influence KSHV replication. We demonstrated that HSV-1 was a potentially important factor in the pathogenesis of KS, as determined by production of lytic phase mRNA transcripts, viral proteins and infectious viral particls in BCBL-1 cells. These results were further confirmed by a luciferase reporter assay testing ORF50 promoter-driven luciferase activity and an RNA interference experiment using small interfering RNA (siRNA) targeting KSHV ORF50. Studies on mechanism showed that HSV-1 induced the production of interleukin-10 (IL-10) and its receptor (IL-10Rα), interleukin-4 (IL-4) and its receptor (IL-4R). Neutralization of IL-10 or IL-4 with corresponding neutralizing antibodies decreased the lytic cycle replication of KSHV by HSV-1. In addition, IL-10/IL-10Ra and IL-4/IL-4R from HSV-1-infected BCBL-1 cells activated PI3K/AKT, ERK MAPK and JAK2 signalings. Addition of LY294002, PI3K inhibitor, peptide II, ERK inhibitor and AG490, JAK2 inhibitor into cell culture significantly decreased the lytic replication of KSHV by HSV-1. These findings suggest that HSV-1 may participate in KS pathogenesis by inducing KSHV replication and increasing KSHV viral load. IL-10、IL-4 and their signalings played an important role in modulation of HSV-1-induced KSHV replication. These data also suggest that the blockage of PI3K/AKT, ERK MAPK and JAK2 signalings may be of therapeutic value in KS patients.
引文
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