Not Interferon, but Interleukin-6 Controls Early Gene Expression in Hepatitis B Virus Infection
Not Interferon, but Interleukin-6 Controls Early Gene Expression in Hepatitis B Virus Infection
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DOI：
10.1002/hep.23226
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发表时间：
2009-12-01
期刊：
影响因子：
13.5
通讯作者：
Protzer, Ulrike
中科院分区：
文献类型：
--
作者：
Hoesel, Marianna;Quasdorff, Maria;Protzer, Ulrike
约有3.5亿病毒携带者，B型肝炎病毒（HBV）感染仍然是一个主要的健康问题。HBV是一种引起持续感染的非细胞病变病毒，但宿主识别HBV是否可以激活先天免疫应答仍不清楚。我们描述了在感染原代人肝细胞后，HBV被肝的非实质细胞识别，主要是肝巨噬细胞（枯否细胞），尽管它们没有被感染。在3小时内，这种识别导致核因子κ B（NF-κ B）的活化，随后释放白细胞介素-6（IL-6）和其他促炎细胞因子（IL-8、TNF-α、IL-1 β），但不诱导干扰素应答。然而，促炎细胞因子的激活是短暂的，甚至抑制对随后的挑战的反应。在感染后不久，NF-κ B B活化后由枯否细胞释放的IL-6在转录水平上控制肝细胞中HBV基因的表达和复制。在与其受体复合物结合后，IL-6激活促分裂原活化蛋白激酶外源性信号调节激酶1/2和c-jun N-末端激酶，其抑制肝细胞核因子（HNF）1 α和HNF 4 α的表达，这两种转录因子是HBV基因表达和复制所必需的。结论：我们的研究结果表明非实质肝细胞识别HBV模式，这导致IL 6介导的HBV感染在转录水平上的控制。因此，IL-6确保了病毒的早期控制，限制了适应性免疫应答的激活并防止HBV感染的肝细胞死亡。这种模式识别对于病毒来说可能是必不可少的，因为病毒只感染了几个病毒体。我们的数据还表明，如果患者是HBV感染者，用于治疗某些疾病的IL-6治疗性中和可能代表风险。（《肝脏病学》2009年;50：1773-1782）
With about 350 million virus carriers, hepatitis B virus (HBV) infection remains a major health problem. HBV is a noncytopathic virus causing persistent infection, but it is still unknown whether host recognition of HBV may activate an innate immune response. We describe that upon infection of primary human liver cells, HBV is recognized by nonparenchymal cells of the liver, mainly by liver macrophages (Kupffer cells), although they are not infected. Within 3 hours, this recognition leads to the activation of nuclear factor kappa B (NF-kappa B) and subsequently to the release of interleukin-6 (IL-6) and other proinflammatory cytokines (IL-8, TNF-alpha, IL-1 beta), but does not induce an interferon response. The activation of proinflammatory cytokines, however, is transient, and even inhibits responsiveness toward a subsequent challenge. IL-6 released by Kupffer cells after activation of NF-kappa B controls HBV gene expression and replication in hepatocytes at the level of transcription shortly after infection. Upon binding to its receptor complex, IL-6 activates the mitogen-activated protein kinases exogenous signal-regulated kinase 1/2, and c-jun N-terminal kinase, which inhibit expression of hepatocyte nuclear factor (HNF) 1 alpha and HNF 4 alpha, two transcription factors essential for HBV gene expression and replication. Conclusion: Our results demonstrate recognition of HBV patterns by nonparenchymal liver cells, which results in IL6-mediated control of HBV infection at the transcriptional level. Thus, IL-6 ensures early control of the virus, limiting activation of the adaptive immune response and preventing death of the HBV-infected hepatocyte. This pattern recognition may be essential for a virus, which infects a new host with only a few virions. Our data also indicate that therapeutic neutralization of IL-6 for treatment of certain diseases may represent a risk if the patient is HBV-infected. (HEPATOLOGY 2009;50:1773-1782.)