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Downregulation of interleukin-18-mediated cell signaling and interferon gamma expression by the hepatitis B virus e antigen

Authors
 S Jegaskanda  ;  S H Ahn  ;  N Skinner  ;  A J Thompson  ;  T Ngyuen  ;  J Holmes  ;  R De Rose  ;  M Navis  ;  W R Winnall  ;  M Kramski  ;  G Bernardi  ;  J Bayliss  ;  D Colledge  ;  V Sozzi  ;  K Visvanathan  ;  S A Locarnini  ;  S J Kent  ;  P A Revill 
Citation
 JOURNAL OF VIROLOGY, Vol.88(18) : 10412-10420, 2014-09 
Journal Title
 JOURNAL OF VIROLOGY 
ISSN
 0022-538X 
Issue Date
2014-09
MeSH
Adult ; Cells, Cultured ; Down-Regulation* ; Female ; Hepatitis B / genetics* ; Hepatitis B / immunology ; Hepatitis B / virology ; Hepatitis B e Antigens / genetics ; Hepatitis B e Antigens / metabolism* ; Hepatitis B virus / genetics ; Hepatitis B virus / metabolism* ; Host-Pathogen Interactions ; Humans ; Interferon-gamma / genetics* ; Interferon-gamma / immunology ; Interleukin-18 / genetics ; Interleukin-18 / metabolism* ; Killer Cells, Natural / immunology ; Male ; Middle Aged ; Signal Transduction ; Young Adult
Abstract
The mechanisms by which hepatitis B virus (HBV) establishes and maintains chronic hepatitis B infection (CHB) are poorly defined. Innate immune responses play an important role in reducing HBV replication and pathogenesis. HBV has developed numerous mechanisms to escape these responses, including the production of the secreted hepatitis B e antigen (HBeAg), which has been shown to regulate antiviral toll-like receptor (TLR) and interleukin-1 (IL-1) signaling. IL-18 is a related cytokine that inhibits HBV replication in hepatoma cell lines and in the liver through the induction of gamma interferon (IFN-γ) by NK cells and T cells. We hypothesized that HBV or HBV proteins inhibit IFN-γ expression by NK cells as an accessory immunomodulatory function. We show that HBeAg protein inhibits the NF-κB pathway and thereby downregulates NK cell IFN-γ expression. Additionally, IFN-γ expression was significantly inhibited by exposure to serum from individuals with HBeAg-positive but not HBeAg-negative chronic HBV infection. Further, we show that the HBeAg protein suppresses IL-18-mediated NF-κB signaling in NK and hepatoma cells via modulation of the NF-κB pathway. Together, these findings show that the HBeAg inhibits IL-18 signaling and IFN-γ expression, which may play an important role in the establishment and/or maintenance of persistent HBV infection. Importance: It is becoming increasingly apparent that NK cells play a role in the establishment and/or maintenance of chronic hepatitis B infection. The secreted HBeAg is an important regulator of innate and adaptive immune responses. We now show that the HBeAg downregulates NK cell-mediated IFN-γ production and IL-18 signaling, which may contribute to the establishment of infection and/or viral persistence. Our findings build on previous studies showing that the HBeAg also suppresses the TLR and IL-1 signaling pathways, suggesting that this viral protein is a key regulator of antiviral innate immune responses.
Files in This Item:
T201406498.pdf Download
DOI
10.1128/JVI.00111-14
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Ahn, Sang Hoon(안상훈) ORCID logo https://orcid.org/0000-0002-3629-4624
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/178497
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