乙型肝炎病毒上调可溶性IL-6受体（sIL-6R）表达对IL-6抗病毒及致炎效应的影响及机制研究

So far, the mechanisms of hepatitis B virus (HBV) persistent infection and host immune responses remained unclear. Recent studies have indicated that HBV infection elicits a limited host innate immune response while HBV has developed a variety of immune evasion strategies. Several reports and our preliminary study have shown that interleukin- 6 (IL-6), a cytokine with multi-biological functions, could be induced in non-parenchymal liver cells upon HBV infection and inhibit the viral replication, however, how the virus modulates the response is yet to be determined. We previously found that the expression level of soluble IL-6 receptor (sIL-6R) in HBV-replicating hepatocytes was significantly upregulated; considering that after binding to IL-6, the sIL-6R could either have a neutralizing activity or promote pro-inflammatory cytokines expression through IL -6 trans-signaling, upregulation of sIL-6R may be an important mechanism for regulating IL-6-activated responses by HBV. Therefore, using multiple in vitro and in vivo models, we propose to further explore the mechanism of the HBV-induced upregulation of sIL-6R and its effect on IL-6-mediated anti-HBV activity in hepatocytes and pro-inflammatory responses in non-parenchymal liver cells. This project will help to deepen the understanding of the immunological significance of the increased expression of sIL-6R, and provide new perspectives to new anti-HBV strategies development.

乙型肝炎病毒（HBV）所致慢性感染的机制仍不明了。近来研究表明宿主对HBV感染会产生一定程度的天然免疫应答，HBV则具有多种逃逸策略。白细胞介素6（IL-6）作为一种多功能的细胞因子，文献及本项目预实验结果均提示其可在HBV感染时由肝非实质细胞分泌并起到抑制HBV复制的作用，而HBV如何调控IL-6效应尚待阐明。申请者前期发现HBV可致肝细胞中可溶性IL-6受体（sIL-6R）的表达显著上调，且sIL-6R结合IL-6后既可表现为中和作用也可经IL-6反式通路促进炎性反应，故考虑sIL-6R的上调可能不仅与HBV逃逸免疫也与HBV感染所继发的炎症相关。拟进一步在体内外模型中，揭示HBV上调sIL-6R表达对IL-6介导的抗HBV及致炎效应的影响，并探索sIL-6R上调机制及其拮抗剂可否逆转HBV对IL-6效应的调控。这将增进对HBV调控宿主免疫的认识，并为开发新型乙肝治疗手段提供理论创见。

乙型肝炎病毒（hepatitis B virus, HBV）是一种肝细胞靶向的病原体，其所引起的急、慢性乙肝等肝脏疾病严重危害着人类健康。迄今为止，HBV持续感染和致病免疫相关机制仍不清楚。近年来研究表明宿主对HBV感染可产生一定程度的天然免疫应答，其中白细胞介素6（IL-6）被报道可在HBV感染时由肝非实质细胞产生并具有抑制肝细胞中HBV复制的作用；另一方面，HBV经过长期演化具备了多种拮抗和逃逸宿主免疫的策略，而对于HBV如何调控IL-6介导的免疫效应仍不清楚。本课题在细胞和病人血清等多层面模型中研究发现HBV感染表达可上调肝细胞IL-6可溶性受体（sIL-6R）的水平，据报道IL-6经由与sIL-6R结合进而激活反式通路是IL-6除通过细胞表面IL-6R经典通路外的另一发挥生物学效应的重要机制，从而丰富了IL-6应答细胞的种类和作用形式。因此，在确认IL-6具有控制HBV感染作用的基础上，本研究观察了sIL-6R上调对IL-6抗HBV及促炎的影响。鉴于IL-6作用于各类细胞经由的受体途径不同，本课题特针对肝细胞和肝非实质细胞受sIL-6R的调控进行了分别研究。结果发现，sIL-6R能够抑制肝细胞中IL-6介导的效应通路（经典通路），而增强肝非实质细胞（包括LSEC肝窦内皮细胞和HSC肝星状细胞）IL-6介导的效应通路（反式通路）。进一步研究发现，HBV可通过上调sIL-6R逃逸肝细胞中IL-6介导的抗HBV反应，而增强肝非实质细胞中的IL-6介导的信号通路，可能与致炎反应相关。进一步探究了HBV介导的sIL-6R表达上调的机制，结果提示HBV可通过上调金属蛋白酶ADAM10的表达从而致使sIL-6R含量升高。本课题首次阐明HBV通过上调sIL-6R逃逸肝细胞中IL-6的抗病毒作用和调控肝非实质细胞IL-6的致炎作用，为人们认识IL-6在HBV建立感染和致病过程中的生物学效应提供了不同的视角，提示病毒有可能通过促进可溶性受体产生的方式来拮抗相关细胞因子的抗病毒功能和促进疾病进展, 从而为开发新型乙肝治疗手段提供新的理论基础和靶点。本课题HBV逃逸天然免疫的结果部分已发表论文1篇，剩余部分尚在进一步深入和整理中；协助培养博士研究生3名，其中先后已有2名毕业。