IL-27, a cytokine, and IFN-λ1, a type III IFN, are coordinated to regulate virus replication through type I IFN

J Immunol. 2014 Jan 15;192(2):691-703. doi: 10.4049/jimmunol.1300252. Epub 2013 Dec 11.

Abstract

IL-27, a member of the IL-12 family, plays a critical role in the control of innate and adaptive immune responses. IFN-λ1, a member of the type III IFN family, shows antiviral abilities. In this study, we investigated the effects of IL-27 and IFN-λ1 on the replication of hepatitis B virus (HBV), a major pathogen associated with a high risk for cirrhosis, liver failure, and hepatocellular carcinoma. We revealed that HBV infection activates IL-27 expression and IFN-λ1 production and demonstrated that viral-activated IL-27 and IFN-λ1 are coordinated to inhibit HBV replication. Initially, HBV infection upregulates IL-27 expression, which, in turn, stimulates IFN-λ1 production through regulating ERK1/2 signaling and by enhancing NF-κB nuclear translocation to bind to the IFN-λ1 promoter. Moreover, IL-27-activated IFN-λ1 upregulates IFN-λ1 receptor (IL-28R1 and IL-10Rβ) activity, resulting in the activation of the STAT1/2 pathway, which, in turn, induces the expression of IFN-stimulated genes, including IFN-inducible dsRNA-activated protein kinase, oligoadenylate synthetase 1, and IFN-induced GTP-binding protein 1 and, finally, inhibits HBV protein expression and viral capsid-associated DNA replication. More interestingly, we also revealed that type I IFN (IFN-α) is also involved in the downregulation of HBV replication mediated by IL-27. Thus, we identified a previously unknown mechanism by which IL-27 and IFN-λ1 are coordinated to regulate virus replication through type I IFN.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Dendritic Cells / metabolism
  • Down-Regulation / genetics
  • Female
  • Hep G2 Cells
  • Hepatitis B virus / genetics
  • Hepatitis B virus / metabolism
  • Hepatitis B, Chronic / genetics
  • Hepatitis B, Chronic / metabolism
  • Hepatitis B, Chronic / virology
  • Hepatocytes / metabolism
  • Humans
  • Interferon Regulatory Factor-7 / genetics
  • Interferon Regulatory Factor-7 / metabolism
  • Interferon-alpha / genetics*
  • Interferon-alpha / metabolism
  • Interferons
  • Interleukins / genetics*
  • Interleukins / metabolism
  • MAP Kinase Signaling System / genetics
  • Male
  • Middle Aged
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Promoter Regions, Genetic / genetics
  • Receptors, Cytokine / genetics
  • Receptors, Cytokine / metabolism
  • Receptors, Interferon
  • Receptors, Interleukin-10 / genetics
  • Receptors, Interleukin-10 / metabolism
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism
  • STAT2 Transcription Factor / genetics
  • STAT2 Transcription Factor / metabolism
  • Up-Regulation / genetics
  • Virus Replication / genetics*

Substances

  • interferon-lambda, human
  • IFNLR1 protein, human
  • IRF7 protein, human
  • Interferon Regulatory Factor-7
  • Interferon-alpha
  • Interleukins
  • MYDGF protein, human
  • NF-kappa B
  • Receptors, Cytokine
  • Receptors, Interferon
  • Receptors, Interleukin-10
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT2 Transcription Factor
  • STAT2 protein, human
  • Interferons