2. Academic Validation
  3. Hepatitis C virus infection induces autocrine interferon signaling by human liver endothelial cells and release of exosomes, which inhibits viral replication

Hepatitis C virus infection induces autocrine interferon signaling by human liver endothelial cells and release of exosomes, which inhibits viral replication

  • Gastroenterology. 2015 Feb;148(2):392-402.e13. doi: 10.1053/j.gastro.2014.10.040.
Silvia Giugliano 1,  Michael Kriss 1,  Lucy Golden-Mason 2,  Evgenia Dobrinskikh 3,  Amy E L Stone 4,  Alejandro Soto-Gutierrez 5,  Angela Mitchell 2,  Salman R Khetani 6,  Daisuke Yamane 7,  Mark Stoddard 8,  Hui Li 8,  George M Shaw 8,  Michael G Edwards 9,  Stanley M Lemon 7,  Michael Gale Jr 4,  Vijay H Shah 10,  Hugo R Rosen 11
Affiliations

Affiliations

  • 1 Division of Gastroenterology and Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado, Denver, Aurora, Colorado.
  • 2 Division of Gastroenterology and Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado, Denver, Aurora, Colorado; Integrated Department in Immunology: University of Colorado Denver and National Jewish Health, Denver, Colorado.
  • 3 Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Denver, Aurora, Colorado.
  • 4 Department of Immunology, University of Washington, School of Medicine, Seattle, Washington.
  • 5 Department of Pathology, Center for Innovative Regenerative Therapies, Department of Surgery, Transplantation Section, Children's Hospital of Pittsburgh, McGowan Institute for Regenerative Medicine and the Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
  • 6 Mechanical and Biomedical Engineering, Colorado State University, Fort Collins, Colorado.
  • 7 Department of Medicine, University of North Carolina, Chapel Hill, North Carolina.
  • 8 Department of Medicine and Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
  • 9 Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Denver, Aurora, Colorado.
  • 10 Mayo Clinic, Division of Gastroenterology and Hepatology, Rochester, Minnesota.
  • 11 Division of Gastroenterology and Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado, Denver, Aurora, Colorado; Integrated Department in Immunology: University of Colorado Denver and National Jewish Health, Denver, Colorado; Eastern Colorado Veteran's Affairs Medical Center, Denver, Colorado. Electronic address: [email protected].
PMID: 25447848 DOI: 10.1053/j.gastro.2014.10.040
Abstract

Background & aims: Liver sinusoidal endothelial cells (LSECs) make up a large proportion of the nonparenchymal cells in the liver. LSECs are involved in induction of immune tolerance, but little is known about their functions during hepatitis C virus (HCV) Infection.

Methods: Primary human LSECs (HLSECs) and immortalized liver endothelial cells (TMNK-1) were exposed to various forms of HCV, including full-length transmitted/founder virus, sucrose-purified Japanese fulminant hepatitis-1 (JFH-1), a virus encoding a luciferase reporter, and the HCV-specific pathogen-associated molecular pattern molecules. Cells were analyzed by confocal immunofluorescence, immunohistochemical, and polymerase chain reaction assays.

Results: HLSECs internalized HCV, independent of cell-cell contacts; HCV RNA was translated but not replicated. Through Pattern Recognition Receptors (Toll-like Receptor 7 and retinoic acid-inducible gene 1), HCV RNA induced consistent and broad transcription of multiple interferons (IFNs); supernatants from primary HLSECs transfected with HCV-specific pathogen-associated molecular pattern molecules increased induction of IFNs and IFN-stimulated genes in HLSECs. Recombinant type I and type III IFNs strongly up-regulated HLSEC transcription of IFN λ3 (IFNL3) and viperin (RSAD2), which inhibit replication of HCV. Compared with CD8(+) T cells, HLSECs suppressed HCV replication within Huh7.5.1 cells, also inducing IFN-stimulated genes in co-culture. Conditioned media from IFN-stimulated HLSECs induced expression of Antiviral genes by uninfected primary human hepatocytes. Exosomes, derived from HLSECs after stimulation with either type I or type III IFNs, controlled HCV replication in a dose-dependent manner.

Conclusions: Cultured HLSECs produce factors that mediate immunity against HCV. HLSECs induce self-amplifying IFN-mediated responses and release of exosomes with Antiviral activity.

Keywords

Cytokine; Immune Regulation; Innate Immunity; Toll-Like Receptor.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15005
    99.97%, HCV Inhibitor
    HCV