IL-32: A Host Proinflammatory Factor against Influenza Viral Replication Is Upregulated by Aberrant Epigenetic Modifications during Influenza A Virus Infection
IL-32: A Host Proinflammatory Factor against Influenza Viral Replication Is Upregulated by Aberrant Epigenetic Modifications during Influenza A Virus Infection
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IL-32：甲型流感病毒感染期间异常表观遗传修饰上调抗流感病毒复制的宿主促炎因子
DOI：
10.4049/jimmunol.0902667
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发表时间：
2010-11-01
影响因子：
4.4
通讯作者：
Zhu, Ying
中科院分区：
文献类型：
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作者：
Li, Wei;Sun, Wei;Zhu, Ying
我们先前的临床数据分析研究表明，促炎因子IL-32在流感病毒感染时被激活。然而，关于流感病毒如何诱导IL-32产生的知之甚少，并且IL-32在病毒感染期间的宿主免疫应答中的作用仍然不清楚。在这项研究中，我们表明，在健康志愿者的人PBMC中，甲型流感病毒或dsRNA刺激IL-32的产生。我们证明NF-κ B和CREB通路在A549人肺上皮细胞响应流感病毒感染的IL-32产生的激活中起关键作用。然后，我们表明，异常表观遗传修饰的IL-32启动子是重要的IL-32表达的转录调控。有趣的是，CREB结合位点内的一个CpG去甲基化增加了CREB与启动子的结合，随后在甲型流感病毒感染的细胞中IL 32转录激活。结合RNA干扰的过表达分析表明，DNA甲基转移酶DNMT 1和DNMT 3b是病毒感染前IL 32启动子甲基化和基因沉默的关键。我们已经证明了IL-32的抗流感病毒功能。在流感病毒感染期间对六种IL-32同种型（α、β、γ、δ、β和ζ）中的每一种的测定表明，所有同种型都具有抗病毒活性，具有不同的抑制率，并且IL-32 γ的作用最强。我们的研究结果表明，流感病毒感染引发的IL-32水平升高反过来阻碍了病毒复制。免疫学杂志，2010，185：5056-5065。
Our previous studies with clinical data analysis have shown that the proinflammatory factor IL-32 is activated in response to influenza virus infection. However, little is known about how influenza virus induces IL-32 production, and the role of IL-32 in the host immune responses during viral infection remains unclear. In this study, we show that IL-32 production is stimulated by influenza A virus or dsRNA in human PBMCs from healthy volunteers. We demonstrate that the NF-kappa B and CREB pathways play key roles in the activation of IL-32 production in response to influenza virus infection in A549 human lung epithelial cells. We then show that aberrant epigenetic modifications in the IL32 promoter are important in the transcriptional regulation of IL-32 expression. Interestingly, one CpG demethylation within the CREB binding site increases the binding of CREB to the promoter, which is followed by IL32 transcriptional activation in influenza A virus-infected cells. Overexpression assays combined with RNA interference show that DNA methyltransferases DNMT1 and DNMT3b are critical for IL32 promoter methylation and gene silencing before viral infection. We have demonstrated the anti-influenza virus function of IL-32. Assays for each of the six IL-32 isoforms (alpha, beta, gamma, delta, epsilon, and zeta) during influenza virus infection indicated that all the isoforms have antiviral activity, with different inhibitory rates, and that the effect of IL-32 gamma is strongest. Our results indicate that the elevated IL-32 levels triggered by influenza virus infection in turn hamper viral replication. The Journal of Immunology, 2010, 185: 5056-5065.