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流感病毒诱导产生白细胞介素35及其抗病毒作用研究
IAV Induced IL-35 Expression and the Antiviral Function of IL-35
【作者】 王莉；
【导师】 朱应；
【作者基本信息】 武汉大学 ， 生物学，微生物学， 2016， 博士
【摘要】 新发现的白细胞介素35由EBI3亚基和p35亚基二聚化形成,是一种可分泌的蛋白质。现有研究认为白细胞介素35是一个促炎症因子具有抑制功能,与炎症疾病、自免疫疾病、以及细胞凋亡有关。目前研究白细胞介素35与病毒感染关系的报道甚少。本论文就A型流感病毒感染诱导白细胞介素35的表达以及白细胞介素35应对病毒感染所发挥的生物学功能进行了初步研究。第一部分研究背景,介绍了白细胞介素35的最新研究进展,综述了白细胞介素12家族成员、转录因子NF-KB和CREB、细胞因子COX-2和iNOS、几种病毒(包括流感病毒、乙肝病毒、肠道病毒EV71、水疱性口炎病毒VSV)、干扰素。第二部分是本文的主要研究内容,研究了A型流感病毒感染上调白细胞介素35的表达及其机制,以及白细胞介素35在病毒感染中的功能。首先我们在季节性流感病人的血液和咽拭子样本中发现白细胞介素35高表达,并且白细胞介素35的表达水平与A型流感病毒的感染水平正相关。然后在细胞水平发现A型流感病毒能够诱导白细胞介素35在肺上皮细胞A549、外周血单个核细胞和人肺泡二型细胞系中表达。进一步研究发现A型流感病毒诱导白细胞介素35的表达通过COX-2和iNOS信号通路,另外在转录水平上起关键调节作用的转录因子是NF-KB/p65。有趣的是,白细胞介素35表现出广谱的从DNA病毒到RNA病毒的抗病毒作用,包括乙型肝炎病毒、流感病毒、水疱性口炎病毒和人肠道病毒71。白细胞介素35的抗病毒机理是通过与受体gp130和IL12Rβ2相互作用,诱导Ⅰ型和Ⅲ型干扰素的产生,并激活下游作用因子PKR、 OAS、Mx。我们的实验结果表明,A型流感病毒通过COX-2和iNOS通路以及转录因子NF-KB/p65正向调控诱导白细胞介素35的表达,同时白细胞介素35在病毒感染过程中又具有广谱的抗病毒作用。我们的发现为白细胞介素35用于潜在的临床治疗病毒感染的应用提供了实验依据。
【Abstract】 The novel IL-35 was a secreted protein which composed of EBI3 and p35. IL-35 has been reported as a pro inflammatory cytokine with inhibitory function, and related with inflammatory diseases, autoimmune diseases and cell apoptosis. However, little is known about the relationship between IL-35 and virus infection. Here we did preliminary research on IAV induced IL-35 expression and the biological function of IL-35 in response to viral infectioaPart 1 introduced the update researches of IL-35 and reviewed the IL-12 family, influenza A virus and interferons.Part 2 is the main research content of this article, describes IAV upregulated IL-35 expression, and the role of IL-35 during viral infection.First, we show that the high expression of IL-35 in the blood and throat swab samples of IAV patients. Then, we found IAV induced IL-35 production in A549, PBMC and AT-Ⅱ cells. Next we investigated that IL-35 was upregulated by IAV via NF-κB/p65 transcription binding site and through COX-2 and iNOS pathways. Interestingly, IL-35 acted anti-viral function to DNA virus like HBV and RNA virus as IAV, EV71 and VSV. IL-35 induced type Ⅰ and type Ⅲ IFN and the downstream factor including PKR, OAS and Mx to inhibit viral infection.Our results suggested that IAV induced IL-35 expression through COX-2 and iNOS pathways and enhancing by NF-κB/p65.Meanwhile, IL-35 played broad-spectrum anti-viral activity. Our study provided theoretical basis for development IL-35 as the potential candidates of anti-viral drugs.