HCV Infection Induces a Unique Hepatic Innate Immune Response Associated With Robust Production of Type III Interferons

Gastroenterology. 2012 Apr;142(4):978-88. doi: 10.1053/j.gastro.2011.12.055. Epub 2012 Jan 13.

Abstract

Background & aims: Polymorphisms in the IL28B gene have been associated with clearance of hepatitis C virus (HCV), indicating a role for type III interferons (IFNs) in HCV infection. Little is known about the function of type III IFNs in intrinsic antiviral innate immunity.

Methods: We used in vivo and in vitro models to characterize the role of the type III IFNs in HCV infection and analyzed gene expression in liver biopsy samples from HCV-infected chimpanzees and patients. Messenger RNA and protein expression were studied in HCV-infected hepatoma cell lines and primary human hepatocytes.

Results: HCV infection of primary human hepatocytes induced production of chemokines and type III IFNs, including interleukin (IL)-28, and led to expression of IFN-stimulated genes (ISGs). Chimpanzees infected with HCV showed rapid induction of hepatic type III IFN, associated with up-regulation of ISGs and minimal induction of type I IFNs. In liver biopsy specimens from HCV-infected patients, hepatic expression of IL-28 correlated with levels of ISGs but not of type I IFNs. HCV infection produced extensive changes with gene expression in addition to ISGs in primary human hepatocytes. The induction of type III IFNs is regulated by IFN regulatory factor 3 and nuclear factor κB. Type III IFNs up-regulate ISGs with a different kinetic profile than type 1 IFNs and induce a distinct set of genes, which might account for their functional differences.

Conclusions: HCV infection results predominantly in induction of type III IFNs in livers of humans and chimpanzees; the level of induction correlates with hepatic levels of ISGs. These findings might account for the association among IL-28, level of ISGs, and recovery from HCV infection and provide a therapeutic strategy for patients who do not respond to IFN therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / therapeutic use
  • Biopsy
  • Cell Line, Tumor
  • Chemokine CXCL10 / metabolism
  • Gene Expression Regulation
  • Hepacivirus / genetics
  • Hepacivirus / immunology*
  • Hepatitis C, Chronic / drug therapy
  • Hepatitis C, Chronic / genetics
  • Hepatitis C, Chronic / immunology*
  • Hepatitis C, Chronic / pathology
  • Hepatocytes / immunology*
  • Hepatocytes / pathology
  • Hepatocytes / virology
  • Humans
  • Immunity, Innate*
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon Type I / metabolism
  • Interferons / genetics
  • Interferons / metabolism*
  • Interleukins / metabolism
  • Liver / immunology*
  • Liver / pathology
  • Liver / virology
  • NF-kappa B / metabolism
  • Pan troglodytes
  • RNA, Messenger / metabolism
  • Signal Transduction
  • Time Factors
  • Up-Regulation

Substances

  • Antiviral Agents
  • CXCL10 protein, human
  • Chemokine CXCL10
  • IFNL2 protein, human
  • IFNL3 protein, human
  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Interferon Type I
  • Interleukins
  • NF-kappa B
  • RNA, Messenger
  • Interferons