Study Of The Regulation Of Hepatitis B Virus On Inflammation Network And Interferon Signaling

Hepatitis B virus (HBV) is a hepadnavirus that can cause hepatitis, cirrhosis, and hepatocellular carcinoma. Until now, the mechanism of HBV infection and pathogenesis are not entirely clear. It is generally acknowledged that the pathogenesis of HBV is different from that of other type of virus because of the various clinical symptoms of hepatitis B (acute hepatitis, chronic active hepatitis, chronic persistent hepatitis, severe hepatitis and asymptomatic HBsAg carrier). The pathology and clinical symptom induced by HBV is probably due to immune response to viral infection. Therefore, the exploration of the interplay between HBV and immune factors, including inflammatory factors and interferon, is the foundation of discovering pathogenic mechanism of HBV and developing novel therapeutics. This study focuses on the regulation of HBV on inflammation network and interferon signaling pathway respectively.Firstly, we discovered that the expression of interleukin-29(IL-29), interleukin-8(IL-8) and cyclooxygenase2(COX-2) was activated by HBV infection in human PBMC and hepatoma cells. Our results further demonstrated that in human lymphocytes and hepatoma cells, IL-29activates the production of IL-8, which in turn enhances the expression of COX-2. In addition, COX-2decreases the production of IL-8, which in turn attenuates the expression of IL-29. Thus, we proposed that HBV infection induces a novel inflammation cytokine network including three inflammatory factors that regulate each other in the order IL-29/IL-8/COX-2, which involves positive regulation and negative feedback.Secondly, in order to elucidate the significance of HBV-induced inflammation network on its infection and pathogenesis, we further investigated the mechanism of the regulation of IL-8on IL-29. We found that IL-8suppressed the transcription and expression of IL-29by downregulation of IRF3and IRF7expression and their binding to the ISRE of IL-29promoter. In addition, IL-8also inhibited the expression of IL-29receptor, IL-10R2and downstream antiviral genes PKR and OAS, ultimately leading to the antagonism of the anti-HBV ability of IL-29.Thirdly, we also uncovered the molecular mechanism of the regulation of IL-8on COX-2. We demonstrated that COX-2expression activated by IL-8was mediated through CREB and C/EBP. IL-8could stimulate the translocation of CREB and C/EBP into nucleus and their binding to COX-2promoter. Finally, we showed that the ERK and the JNK signaling pathways were cooperatively involved in the regulation of COX-2.In a word, HBV induces a novel inflammation network. IL-8, as the core mediator of this network, not only impairs the antiviral activity of IL-29and favors the establishment of persistent viral infection but also induces the high expression of proinflammatory factor COX-2to maintain the inflammatory environment associated with HBV infection. These new findings provide insights for our understanding of the pathogenic mechanism of HBV infection and allow more rational development of immunotherapeutic strategies.The interferon response is one of the host response’s primary defense mechanisms against viral infection. Interferon has been widely used in the treatment of hepatitis B because of its immunomodulatory and antiviral activities. However, the low response to interferon-α (IFNα) of patients suffering chronic hepatitis B suggests that HBV has evolved effective strategies to counteract the action of IFN. So next, we deeply investigated the mechanism underlying HBV regulation of interferon signaling.Our results showed that HBV e antigen (HBeAg) interferes with the IFNa and IFNλ, activated JAK/STAT signaling pathways. Furthermore, HBeAg impaired IFNα/IFNλ,-induced STAT1tyrosine phosphorylation and nuclear translocation. We also demonstrated HBeAg suppressed the expression of IFNα/IFNλ,-activated antiviral genes, MxA, OAS and PKR and in turn attenuated the anti-HBV activities of IFNα and IFNλ in HepG2cells. Finally, we discovered that HBeAg activated the expression of suppressor of cytokine signaling2(SOCS-2) which played an indispensable role in the HBeAg dysregulation of IFNα/IFNλ,-induced JAK/STAT signaling. Taken together, our numerous results show that HBV can create a benefit environment for its own survival and persistence through the induction of a complex inflammation network or dysregulation of interferon signaling by viral protein, which may be one of the pathogenic mechanisms of HBV infection.