Retinoic acid inducible gene-I (RIG-I) signaling of hepatic stellate cells inhibits hepatitis C virus replication in hepatocytes

Abstract

Retinoic acid inducible gene-I (RIG-I) is critical in the activation of the type I IFN-dependent antiviral innate immune response to hepatitis C virus (HCV) infection. We examined whether hepatic stellate cells (HSC; LX-2) possess a functional RIG-I signaling pathway and produce antiviral factors that can inhibit HCV. We showed that LX-2 cells treated with the RIG-I ligand (5′ppp-dsRNA) expressed significantly higher levels of IFN-β and IFN-λ than the control cells. The RIG-I activation in LX-2 cells also induced the expression of Toll-like receptor 3 (TLR3) and IFN regulatory factor-7 (IRF-7), the key regulators of the IFN signaling pathway. When HCV Japanese fulminant hepatitis (JFH)-1-infected hepatocytes were co-cultured with LX-2 cells stimulated with 5′ppp-dsRNA or incubated in media conditioned with supernatant (SN) from 5′ppp-dsRNA-stimulated LX-2 cells, HCV replication in hepatocytes was suppressed significantly. This LX-2 cell action on HCV replication was mediated through both IFN-β and IFN-λ, as Abs to IFN-α/β or IFN-λ receptors could neutralize the LX-2 SN-mediated anti-HCV effect. The role of IFNs in LX-2 cell-mediated anti-HCV activity is further supported by the observation that LX-2 SN treatment induced the expression of IFN stimulated genes, 2′-5′-oligoadenylate synthase-1 (OAS-1) and myxovirus resistance A (MxA), in HCV-infected Huh7 cells. These observations highlight the importance of HSC in liver innate immunity against HCV infection via a RIG-I-mediated signaling pathway.

Hepatic stellate cells, liver innate immunity, and hepatitis C virus

“…Although great progress has been made in the research field of HSCs and liver fibrosis, limited information is available about the role of HSCs in liver immunity. As shown in Table , recent studies by several groups have clearly shown that HSCs are involved in the regulation of liver immunity. It was shown that HSCs could act as a regulatory bystander, enhancing differentiation and accumulation of Tregs .…”

“…We demonstrated that HSCs (LX‐2 cells) possess functional RIG‐I that can be activated by the RIG‐I ligand, resulting in the induction of IFNs and inhibition of HCV replication in hepatocytes . This RIG‐I signaling‐mediated anti‐HCV activity was potent, as when HCV JFH‐1‐infected hepatocytes were co‐cultured with RIG‐I‐activated LX‐2 cells or incubated in media conditioned with supernatant (SN) from RIG‐I‐activated LX‐2 cells, HCV replication in hepatocytes was significantly suppressed . Further investigation showed that RIG‐I‐activated LX‐2 cells produced both type I IFN (IFN‐β) and type III IFN (IFN‐λ) .…”

“…However, we know little about whether HSCs possess functional RIG‐I signaling pathway and produce anti‐HCV factors. Our recent studies examined whether HSCs have the ability to mount a RIG‐I‐mediated innate immunity that is effective in the control of HCV infection of human hepatocytes . We demonstrated that HSCs (LX‐2 cells) possess functional RIG‐I that can be activated by the RIG‐I ligand, resulting in the induction of IFNs and inhibition of HCV replication in hepatocytes .…”

“…Our recent studies examined whether HSCs have the ability to mount a RIG‐I‐mediated innate immunity that is effective in the control of HCV infection of human hepatocytes . We demonstrated that HSCs (LX‐2 cells) possess functional RIG‐I that can be activated by the RIG‐I ligand, resulting in the induction of IFNs and inhibition of HCV replication in hepatocytes . This RIG‐I signaling‐mediated anti‐HCV activity was potent, as when HCV JFH‐1‐infected hepatocytes were co‐cultured with RIG‐I‐activated LX‐2 cells or incubated in media conditioned with supernatant (SN) from RIG‐I‐activated LX‐2 cells, HCV replication in hepatocytes was significantly suppressed .…”

Lambda-Interferons Inhibit Herpes Simplex Virus Type 2 Replication in Human Cervical Epithelial Cells by Activating the JAK/STAT Pathway

“…This com-plex binds to the IFN-stimulated response element and induces ISGs, which play important roles in IFN-mediated antiviral activity (1,15). The potential clinical importance of IFN-s as novel antiviral therapeutic agents has recently become apparent (1,5,(16)(17)(18)(19).…”