Transforming growth factor β-activated kinase 1 transcriptionally suppresses hepatitis B virus replication

Zhang

Journal of Medical Virology

et al. 2019

Increasing evidence indicates ATP1B3, one of the regulatory subunits of Na+/K+‐ATPase, is involved in numerous viral propagations, such as HIV and EV71. However, the function and mechanism of ATP1B3 on hepatitis B virus (HBV) propagation is unknown. Here, we demonstrated that ATP1B3 overexpression reduced the quantity of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) in supernatants of HBV expression plasmids cotransfected HepG2 cells. Correspondingly, small interfering RNA and short hairpin RNA mediated ATP1B3 silencing promoted HBsAg and HBeAg expression in the supernatants of HBV expression plasmids transfected HepG2 cells. Mechanically, we reported that ATP1B3 expression could activate nuclear factor‐κB (NF‐κB) pathway by inducing the expression, phosphorylation, and nuclear import of P65 for the first time. And NF‐κB inhibitor (Bay11) impaired the restraint of ATP1B3 on HBV replication. This counteraction effect of Bay11 proved that ATP1B3‐induced NF‐κB activation was crucial for HBV restriction. Accordingly, we observed that anti‐HBV factors interferon‐α (IFN‐α) and interleukin‐6 (IL‐6) production were increased in HepG2 cells after the NF‐κB activation. It suggested that ATP1B3 suppressed HBsAg and HBeAg by NF‐κB/IFN‐α and NF‐κB/IL‐6 axis. Further experiments proved that ATP1B3 overexpression induced anti‐HBV factor BST‐2 expression by NF‐κB/IFN‐α axis in HepG2 cells but not HEK293T cells, and ATP1B3 silencing downregulated BST‐2 messenger RNA level in HepG2 cells. As an HBV restriction factor, BST‐2 cooperated with ATP1B3 to antagonize HBsAg but not HBeAg in HepG2 cells. Our work identified ATP1B3 as a novel candidate of HBV restrictor with unrevealed mechanism and we highlighted it might serve as a potential therapeutic molecule for HBV infection.

Section: Discussionmentioning

confidence: 99%

ATP1B3 cooperates with BST‐2 to promote hepatitis B virus restriction

Zhang

Journal of Medical Virology

et al. 2019

“…As such, TLR4 activation in PWHs by LPS led to a suppressed WHV replication in an IFN-independent manner [ 51 ]. Our recent study validated this hypothesis by demonstrating that overexpression transforming growth factor β-activated kinase 1 (TAK1), a key adaptor in TLR-mediated signaling pathway, efficiently inhibited HBV replication in vitro and in vivo [ 52 ].…”

Section: Inhibition Of Hbv Replication By Tlr-mediated Innate Immumentioning

confidence: 96%

Interaction between Hepatitis B Virus and Toll-Like Receptors: Current Status and Potential Therapeutic Use for Chronic Hepatitis B

Cao

Xiong

et al. 2018

Vaccines

Self Cite

Immune defense against infection with the hepatitis B virus (HBV) is complex and involves both host innate and adaptive immune systems. It is well accepted that the development of sufficient HBV-specific T cell and B cell responses are required for controlling an HBV infection. However, the contribution of innate immunity to removing HBV has been explored in recent years. Toll-like receptors (TLRs) are recognized as the first line of antiviral immunity because they initiate intracellular signaling pathways to induce antiviral mediators such as interferons (IFNs) and other cytokines. Recent studies show that the activation of TLR-mediated signaling pathways results in a suppression of HBV replication in vitro and in vivo. However, HBV has also evolved strategies to counter TLR responses including the suppression of TLR expression and the blockage of downstream signaling pathways. Antiviral treatment in chronic HBV-infected patients leads to an upregulation of TLR expression and the restoration of its innate antiviral functions. Thus, TLR activation may serve as an additional immunotherapeutic option for treating chronic HBV infection in combination with antiviral treatment.

“…Growing evidence supported that cytokine-mediated immune response plays an important role in clinical outcomes of HBV infection 3 4 . Many immune factors were involved in the HBV infection including classical immune factors, transforming growth factor-β (TGF-β) 5 , tumor necrosis factor-α (TNF-α) 6 , and members of the interleukin family such as interleukin-6 7 and interluekin-23 8 .…”

Section: Introductionmentioning

confidence: 99%

Interleukin-35 Level Is Reduced in Patients with Chronic Hepatitis B Virus Infection

et al. 2018

Backgrounds: As one of the major public health problems, the hepatitis B virus (HBV) infection would activate the immune system. The outcome of HBV infection was affect significantly by the interactions between HBV and host immune response. Interleukins play important role in anti-viral immunity. Here we investigated the role of interleukin-35 (IL-35) in chronic HBV infection patients.Methods/Results: Serum IL-35 in 72 chronic hepatitis B virus infection patients and 41 healthy control subjects were analyzed by ELISA assay. The mRNA level of IL-35 in PBMCs was determined by RT-qPCR. In this study, we found that both protein and mRNA levels of IL-35 were significantly decreased in chronic HBV patients compared to the healthy controls. Furthermore, the statistical analysis found that serum IL-35 was significantly associated with HBV DNA (P =0.0158), ALT (P =0.0003), AST (P =0.0216), TB (P =0.0270) and AFP (P =0.0369). Importantly, correlation analysis also found that serum IL-35 level was negatively correlated with HBV DNA copies, ALT, AST, TB and AFP. Meanwhile, IL-35 treatment inhibited the level of HBV DNA, HBsAg and HBeAg in HepAD38 cells.Conclusion: Our study identified that IL-35 may be a novel marker associated with HBV infection and hepatocytes injury. These data suggested the potential use of IL-35 in the HBV treatment.