Regulation of interferon signaling and HCV‑RNA replication by extracellular matrix

Abstract

Although interferon (IFN)-based treatment of patients with chronic hepatitis C virus (HCV) infection is widely applied, treatment resistance is often observed in patients with advanced liver fibrosis. Given that the molecular mechanisms of IFN resistance in liver fibrosis remain elusive, the present study investigated the effects of extracellular matrix (ECM) on IFN signaling in hepatic cells. The native HuH-7 human hepatoma cell line and HuH-7 cells were stably transfected with full-length HCV-RNA fused with Renilla luciferase (OR6 cells) were cultured on ECM-coated dishes or non-coated plastic dishes (NDs), and treated with human IFN-α. In Huh-7 cells cultured on coated dishes, the IFN-stimulated response element (ISRE) luciferase activity was measured following ISRE plasmid transfection and the expression of IFN-stimulated genes (ISG) were significantly lower than those in cells cultured on NDs. In addition, after IFN-α treatment, the amount of HCV-RNA and viral protein produced by OR6 cells cultured on coated dishes was higher than that produced by cells cultured on NDs. When cells were treated with β1-integrin-blocking antibody to disrupt the cell-matrix interaction, the ISRE luciferase activity was restored, and the protein expression of ISG was increased, while that of HCV proteins was suppressed. Treatment of cells with integrin-linked kinase (ILK) inhibitor or focal adhesion kinase (FAK) inhibitor restored the ISRE luciferase activity and expression of ISG proteins. These results suggested that β1-integrin-mediated signals affected the IFN signaling and promoted HCV replication. Therefore, the accumulation of ECM in liver fibrosis may impair IFN signaling through β1-integrin-mediated signaling involving ILK and FAK.

MicroRNA Profile of HCV Spontaneous Clarified Individuals, Denotes Previous HCV Infection

“…This pathway is involved in liver fibrosis development, which is triggered by an HCV infection through the activation of hepatic stellate cells (HSCs) [54]. The ECM is involved in the regulation of the interferon signaling pathway and HCV-RNA replication [55]. PBMCs contribute to systemic and regional inflammation and matrix remodeling in some model diseases, such as cardiac disease [56] and obesity [57].…”

Bayesian approach for predicting responses to therapy from high-dimensional time-course gene expression profiles

“…Previous studies have suggested that angiotensin II [ 38 ] and fibrogenic cytokines [ 39 ] contributed to the production of extracellular matrix in the liver. It was reported that excessive accumulation of extracellular matrix components, such as fibrillar type I and III collagens, fibronectin, and laminin, is a feature of liver fibrosis [ 40 , 41 ]. Another study reported that the accumulation of extracellular matrix in liver fibrosis might impair the signaling of interferon used as therapy [ 40 ].…”

“…It was reported that excessive accumulation of extracellular matrix components, such as fibrillar type I and III collagens, fibronectin, and laminin, is a feature of liver fibrosis [ 40 , 41 ]. Another study reported that the accumulation of extracellular matrix in liver fibrosis might impair the signaling of interferon used as therapy [ 40 ]. Regarding disulfide bonds, it was reported that a disulfide bond core protein complex might constitute the nucleocapsid-like particle of HCV [ 42 ].…”

Transcriptome and MicroRNAs Profiling Analysis of Huh7.5.1 Cells in Response to Hepatitis C Virus Infection

“…It suggested that β1-integrin-mediated signals affected the IFN signaling and promoted HCV replication. Therefore, the accumulation of extracellular matrix (ECM) in liver fibrosis may impair IFN signaling through β1integrin-mediated signaling involving ILK and FAK (38). In addition, the facilitation of HCV replication by Tax protein may partially account for more severe clinical consequences of HCV-related disease in HCV/HTLV co-infected individuals (39).…”