(−)-Epigallocatechin-3-Gallate Enhances Hepatitis C Virus Double-Stranded RNA Intermediates-Triggered Innate Immune Responses in Hepatocytes

Abstract

(−)-Epigallocatechin-3-gallate (EGCG), a major polyphenol component of green tea, has recently been identified as an inhibitor of hepatitis C virus (HCV) entry. Here, we examined whether EGCG can enhance hepatocyte-mediated intracellular innate immunity against HCV. HCV dsRNAs (Core, E1-P7, NS-3′NTR and NS5A) induced interferon-λ1 (IFN-λ1) expression in human hepatocytes. These HCV dsRNAs also induced the expression of Toll-like receptor 3 (TLR3), retinoic acid-inducible gene I (RIG-I) and several antiviral IFN-stimulated genes (ISGs) expression. Although EGCG treatment of hepatocytes alone had little effect on TLR3 and RIG-I signaling pathways, EGCG significantly enhanced HCV dsRNAs-induced the expression of IFN-λ1, TLR3, RIG-I and antiviral ISGs in hepatocytes. Furthermore, treatment of HCV-infected hepatocytes with EGCG and HCV dsRNAs inhibited viral replication. Given that EGCG has the ability to enhance HCV dsRNAs-induced intracellular antiviral innate immunity against HCV, suggesting the potential application of EGCG as a new anti-HCV agent for HCV therapy.

Therapeutic Potential of Epigallocatechin Gallate Nanodelivery Systems

“…EGCG is also useful in the inhibition of other viruses, such as enterovirus 71, hepatitis C, adenovirus, herpes simplex virus, and influenza virus [ 24 , 97 – 100 ]. One of the molecular targets that seem to be deregulated by the viral infection is the NF-kB and the MAP-kinases pathway [ 101 – 105 ].…”

(-)-Epigallocatechin-3-gallate enhances poly I:C-induced interferon-λ1 production and inhibits hepatitis C virus replication in hepatocytes

“…In order to test the effect of EGCG on poly I:C-induced IFN-λ1 expression, we treated JFH-1-Huh7 cells (72 h post-infection) with EGCG (1-10 μmol/L) for 1 h before poly I:C treatment. The data showed that EGCG could significantly increase poly I:C-mediated IFN- λ 1 mRNA expression (Figure 1A ), as well as IFN-λ1 protein production (Figure 1B ), in a dose-dependent manner, whereas EGCG treatment alone had a negligible effect on IFN-λ1 expression in JFH-1-infected Huh7 cells[ 32 ].…”

“…TLR3 and RIG-I are major cellular receptors that recognize pathogen-associated molecular patterns (PAMPs) during RNA virus infections. While EGCG (at a concentration lower than 10 μmol/L) treatment alone showed little effect on TLR3 and RIG-I expression[ 32 ], EGCG significantly increased the poly I:C-induced mRNA expression of TLR3 (Figure 2A ) and RIG-I (Figure 2B ) in JFH-1-Huh7 cells.…”

“…Our previous study[ 32 ] showed that when we treated JFH-1-Huh7 cells with EGCG (1-10 μmol/L) alone, EGCG could not inhibit viral replication. We found that poly I:C treatment also had limited antiviral effect on the HCV-infected Huh7 cells (Figure 3 ).…”

“…Our recent study showed that HCV replication could impair the polyinosinic-polycytidylic acid (poly I:C)-triggered intracellular innate immune signaling pathway in hepatocytes[ 31 ]. Furthermore, we showed that EGCG possesses the ability to increase HCV dsRNA intermediate-induced expression of IFN-λ1 and IFN-stimulated genes (ISGs)[ 32 ]. In this study, we investigated the effect of EGCG on poly I:C-induced IFN pathway activation and its antiviral activities.…”