Downregulation of Interleukin-18-Mediated Cell Signaling and Interferon Gamma Expression by the Hepatitis B Virus e Antigen
Downregulation of Interleukin-18-Mediated Cell Signaling and Interferon Gamma Expression by the Hepatitis B Virus e Antigen
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DOI：
10.1128/jvi.00111-14
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发表时间：
2014-09-01
影响因子：
5.4
通讯作者：
Revill, P. A.
中科院分区：
文献类型：
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作者：
Jegaskanda, S.;Ahn, S. H.;Revill, P. A.
乙肝病毒(HBV)建立和维持慢性乙肝感染(CHB)的机制尚不清楚。先天免疫反应在减少乙肝病毒复制和致病中起着重要作用。乙肝病毒已发展出许多机制来逃避这些反应，包括产生分泌型乙肝e抗原(HBeAg)，它已被证明调节抗病毒Toll样受体(TLR)和白介素1(IL-1)信号。IL-18是一种相关的细胞因子，可通过NK细胞和T细胞诱导产生干扰素(IFN-γ)来抑制乙肝病毒在肝癌细胞系和肝脏中的复制。我们假设，作为一种辅助免疫调节功能，乙肝病毒或乙肝病毒蛋白抑制NK细胞的干扰素-γ的表达。我们发现HBeAg蛋白抑制了核因子-γB途径，从而下调了NK细胞干扰素-γ的表达。此外，接触HBeAg阳性而不是HBeAg阴性的慢性乙肝病毒感染者的血清可显著抑制干扰素-γ的表达。进一步，我们发现HBeAg蛋白通过调节NF-kappa B途径抑制IL-18介导的NK细胞和肝癌细胞中的NF-kappa B信号转导。综上所述，这些发现表明，HBeAg抑制IL-18信号和干扰素-γ的表达，这可能在慢性乙肝持续感染的建立和/或维持中发挥重要作用。分泌的HBeAg是先天免疫和获得性免疫反应的重要调节因子。我们现在发现，HBeAg下调NK细胞介导的干扰素-kappa的产生和IL-18信号，这可能有助于建立感染和/或病毒持久性。我们的发现建立在先前研究的基础上，研究表明HBeAg还抑制TLR和IL-1信号通路，表明这种病毒蛋白是抗病毒天然免疫反应的关键调节因子。
The mechanisms by which hepatitis B virus (HBV) establishes and maintains chronic hepatitis B infection (CHB) are poorly defined. Innate immune responses play an important role in reducing HBV replication and pathogenesis. HBV has developed numerous mechanisms to escape these responses, including the production of the secreted hepatitis B e antigen (HBeAg), which has been shown to regulate antiviral toll-like receptor (TLR) and interleukin-1 (IL-1) signaling. IL-18 is a related cytokine that inhibits HBV replication in hepatoma cell lines and in the liver through the induction of gamma interferon (IFN-gamma) by NK cells and T cells. We hypothesized that HBV or HBV proteins inhibit IFN-gamma expression by NK cells as an accessory immunomodulatory function. We show that HBeAg protein inhibits the NF-gamma B pathway and thereby downregulates NK cell IFN-gamma expression. Additionally, IFN-gamma expression was significantly inhibited by exposure to serum from individuals with HBeAg-positive but not HBeAg-negative chronic HBV infection. Further, we show that the HBeAg protein suppresses IL-18-mediated NF-kappa B signaling in NK and hepatoma cells via modulation of the NF-kappa B pathway. Together, these findings show that the HBeAg inhibits IL-18 signaling and IFN-gamma expression, which may play an important role in the establishment and/or maintenance of persistent HBV infection.IMPORTANCEIt is becoming increasingly apparent that NK cells play a role in the establishment and/or maintenance of chronic hepatitis B infection. The secreted HBeAg is an important regulator of innate and adaptive immune responses. We now show that the HBeAg downregulates NK cell-mediated IFN-kappa production and IL-18 signaling, which may contribute to the establishment of infection and/or viral persistence. Our findings build on previous studies showing that the HBeAg also suppresses the TLR and IL-1 signaling pathways, suggesting that this viral protein is a key regulator of antiviral innate immune responses.