Transforming growth factor-β1 suppresses hepatitis B virus replication primarily through transcriptional inhibition of pregenomic RNA

Abstract

Transforming growth factor-beta1 (TGF-␤1) is a pleiotropic cytokine with pivotal roles in the regulation of cellular functions and immune responses. In this study, we found that TGF-␤1 was able to effectively suppress hepatitis B virus (HBV) replication. In the presence of TGF-␤1, the level of viral replicative intermediates was dramatically decreased, both in actively dividing cells and in confluent cells. At the same time, the levels of viral transcripts, core protein, and nucleocapsid were significantly diminished by TGF-␤1 treatment. Interestingly, the inhibitory activity of TGF-␤1 was associated with preferential reduction of the level of pregenomic RNA compared with pre-C mRNA. [3][4][5] It has been demonstrated that during HBV infection viral clearance occurs before destruction of infected hepatocytes in both the chimpanzee and the transgenic mouse model. 6,7 Some experimental results have implied that cytokines are involved in the suppression of HBV replication noncytopathically. Clinical observations indeed have revealed several cytokines to be elevated during the progression of hepatitis. 8 These cytokines are likely to be involved in the regulation of immune responses against viral infection and may directly inhibit viral replication. Recently, several cytokines including IL-18, IFNs, and TNF-␣ have been reported to be effective in the suppression of HBV replication both in the livers of HBV transgenic mice and in a cell culture system. 9-12 However, the effect of TGF-␤1, which is the major cytokine secreted by hepatocytes and nonparenchymal cells, on HBV replication has not been studied. Abbreviations: cccDNA, covalently closed circular DNA; HBcAg, HBV core protein; HBeAg, HBV e antigen; pgRNA, pregenomic RNA; From the

Cytokine-Mediated Immunopathogenesis of Hepatitis B Virus Infections

“…In a CHB patient, inhibition of IL-10 with or without TGF-β was able to restore the cytotoxic capacity of liver NK cells to produce IFN-γ, thereby enhancing their noncytolytic antiviral capacity [137]. TGF-β1 treatment was able to effectively suppress HBV replication and the levels of viral transcripts, core protein, and nucleocapsid [32,138]; hence, TGF-β-based immunotherapy needs further exploration to achieve an optimal therapeutic regimen for HBV patients. Previous data have proposed that injection of granulocytemacrophage colony-stimulating factor (GM-CSF), known to be a good adjuvant for vaccination, before the vaccine might promote a stronger immune response in humans [139]; recombinant human GM-CSF significantly reduced hepatitis B virus DNA levels [140].…”

Involvement of Interleukin 6 in Hepatitis B Viral Infection

“…The first class including IL-4 [55] and TGF-β1 [56] inhibits viral gene expression, and subsequently suppresses HBV replication. The second class (Types I and II IFN [57] and TNF-α [58]) destabilizes viral genome-containing capsids or prevents their assembly.…”

Entecavir combined with furin inhibitor simultaneously reduces hepatitis B virus replication and e antigen secretion

“…HBV replication enhancements of CMK and the mutation (T147A) are accompanied by intracellular HBcAg accumulation [16], and HBcAg is structural protein with its intracellular level usually correlating with viral replication level [18, 19]. The findings support that HBcAg accumulation accounts for the HBV replication enhancement of CMK and the mutation.…”

“…CMK has been found to accumulate intracellular HBcAg in the cells transfected with HBeAg-defective variants of HBV [16], and the level of intracellular HBcAg usually correlates the level of HBV replication [18, 19], suggest that HBcAg accumulation may be responsible for HBV replication enhancement. In this study, the effect of CMK was investigated in HBeAg-competent HepG2.2.15 cells.…”