Antiviral activity of various interferons and pro-inflammatory cytokines in non-transformed cultured hepatocytes infected with hepatitis B virus
Antiviral activity of various interferons and pro-inflammatory cytokines in non-transformed cultured hepatocytes infected with hepatitis B virus
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DOI：
10.1016/j.antiviral.2016.03.008
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发表时间：
2016-06-01
影响因子：
7.6
通讯作者：
Durantel, David
中科院分区：
文献类型：
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作者：
Isorce, Nathalie;Testoni, Barbara;Durantel, David
在HBV感染的患者中，核苷类似物或IFN α治疗在根除感染方面仍然无效。我们的目的是重新分析一个大面板的干扰素和细胞因子在体外使用非转化培养的肝细胞感染HBV的抗HBV活性，以确定新的immunethealthy选项。HepaRG细胞和原代人肝细胞感染HBV，并在感染建立时，用不同浓度的不同干扰素或炎性细胞因子处理。通过qPCR和Southern Blot定量HBV核酸评估病毒参数，并使用ELISA评估分泌的HBV抗原，测试的细胞因子是I型IFN、IFN γ、III型IFN、TNF α、IL-6、IL-1 β、IL-18以及核苷（酸）类似物替诺福韦和利巴韦林。除IL-18和利巴韦林外，细胞因子和药物对HBV复制的抑制作用至少与IFN α一样强，但往往强于IFN α。对HBV DNA影响最大的细胞因子是IL-1 β，其抑制作用在皮摩尔范围内。重要的是，我们注意到IFN和炎性细胞因子对其他参数（HBV RNA，HBeAg，HBeAg）的不同影响，从而表明不同的作用机制。IL-1 β和已经使用的疗法（即IFN α或替诺福韦）的组合显示出更强或相似的抗HBV活性。HBV先前显示出迅速抑制库普弗细胞中IL-1 β的产生。旨在解除这种抑制并恢复IL-1 β局部产生的策略可能有助于进一步抑制体内HBV复制。(C)2016爱思唯尔B.V.保留所有权利。
In HBV-infected patients, therapies with nucleoside analogues or IFN alpha remain ineffective in eradicating the infection. Our aim was to re-analyze the anti-HBV activity of a large panel of IFNs and cytokines in vitro using non-transformed cultured hepatocytes infected with HBV, to identify new immunetherapeutic options.HepaRG cells and primary human hepatocytes were infected with HBV and, when infection was established, treated with various concentrations of different IFNs or inflammatory cytokines. Viral parameters were evaluated by quantifying HBV nucleic acids by qPCR and Southern Blot, and secreted HBV antigens were evaluated using ELISA.The cytokines tested were type-I IFNs, IFN gamma, type-III IFNs, TNF alpha, IL-6, IL-1 beta, IL-18 as well as nucleos(t)ide analogues tenofovir and ribavirin. Cytokines and drugs, with the exception of IL-18 and ribavirin, exhibited a suppressive effect on HBV replication at least as strong as, but often stronger than, IFN alpha. The cytokine presenting the highest effect on HBV DNA was IL-1 beta, which exerted its inhibition within picomolar range. Importantly, we noticed differential effects on other parameters (HBV RNA, HBeAg, HBeAg) between both IFNs and inflammatory cytokines, thus suggesting different mechanisms of action. The combination of IL-1 beta and already used therapies, i.e. IFN alpha or tenofovir, demonstrated a stronger or similar anti-HBV activity.IL-1 beta was found to have a very potent antiviral effect against HBV in vitro. HBV was previously shown to promptly inhibit IL-1 beta production in Kupffer cells. Strategies aiming at unlocking this inhibition and restoring local production of IL-1 beta may help to further inhibit HBV replication in vivo. (C) 2016 Elsevier B.V. All rights reserved.