title: Induction of IFN-λ3 as an additional effect of nucleotide, not nucleoside, analogues: a new potential target for HBV infection.
abstract: The clinical significance of polymorphisms in the interleukin-28B gene encoding interferon (IFN)-λ3, which has antiviral effects, is known in chronic HCV but not in HBV infection. Thus, we measured IFN-λ3 levels in patients with HBV and investigated its clinical significance and association with nucleos(t)ide (NUC) analogue administration.
  
  
  
  Serum IFN-λ3 level was measured in 254 patients with HBV with varying clinical conditions using our own high sensitivity method. The resulting values were compared with various clinical variables. In addition, cell lines originating from various organs were cultured with NUCs, and the production of IFN-λ3 was evaluated.
  
  
  
  Higher serum IFN-λ3 levels were detected in the patients treated with nucleotide analogues (adefovir or tenofovir) compared with those treated with nucleoside analogues (lamivudine or entecavir). There were no other differences in the clinical background between the two groups. A rise in the serum IFN-λ3 levels was observed during additional administration of the nucleotide analogues. In vitro experiments showed that the nucleotide analogues directly and dose-dependently induced IFN-λ3 production only in colon cancer cells. Furthermore, the supernatant from cultured adefovir-treated colon cancer cells significantly induced IFN-stimulated genes (ISGs) and inhibited hepatitis B surface antigen (HBsAg) production in hepatoma cells, as compared with the supernatant from entecavir-treated cells.
  
  
  
  We discovered that the nucleotide analogues show an additional pharmacological effect by inducing IFN-λ3 production, which further induces ISGs and results in a reduction of HBsAg production. These findings provide novel insights for HBV treatment and suggest IFN-λ3 induction as a possible target.
authors: The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.
authors: Kazumoto
authors: K
authors: Murata
authors: The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.|Department of Hepatitis and Immunology, Nagoya City University Graduate School of Medical Science, Nagoya, Japan.
authors: Mai
authors: M
authors: Asano
authors: Department of Medicine, Shinshu University of Medicine, Matsumoto, Japan.
authors: Akihiro
authors: A
authors: Matsumoto
authors: The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.
authors: Masaya
authors: M
authors: Sugiyama
authors: The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.
authors: Nao
authors: N
authors: Nishida
authors: Department of Medicine, Shinshu University of Medicine, Matsumoto, Japan.
authors: Eiji
authors: E
authors: Tanaka
authors: First Department of Medicine, University of Yamanashi, Chuo, Japan.
authors: Taisuke
authors: T
authors: Inoue
authors: First Department of Medicine, University of Yamanashi, Chuo, Japan.
authors: Minoru
authors: M
authors: Sakamoto
authors: First Department of Medicine, University of Yamanashi, Chuo, Japan.
authors: Nobuyuki
authors: N
authors: Enomoto
authors: Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors: Takayoshi
authors: T
authors: Shirasaki
authors: Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors: Masao
authors: M
authors: Honda
authors: Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors: Shuichi
authors: S
authors: Kaneko
authors: AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.
authors: Hiroyuki
authors: H
authors: Gatanaga
authors: AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.
authors: Shinichi
authors: S
authors: Oka
authors: Department of Gastroenterology, The Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Ichikawa, Japan.
authors: Yuki I
authors: YI
authors: Kawamura
authors: Department of Gastroenterology, The Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Ichikawa, Japan.
authors: Taeko
authors: T
authors: Dohi
authors: Division of Colorectal Surgery, Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan.
authors: Yasutaka
authors: Y
authors: Shuno
authors: Division of Colorectal Surgery, Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan.
authors: Hideaki
authors: H
authors: Yano
authors: The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.|Department of Hepatitis and Immunology, Nagoya City University Graduate School of Medical Science, Nagoya, Japan.
authors: Masashi
authors: M
authors: Mizokami
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D058345:Asymptomatic Infections; D006528:Carcinoma, Hepatocellular / Q000097:blood*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004279:DNA, Viral / Q000097:blood; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005838:Genotype; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D019073:HT29 Cells; D056945:Hep G2 Cells; D006514:Hepatitis B Surface Antigens / Q000378:metabolism; D006515:Hepatitis B virus / Q000235:genetics; D019694:Hepatitis B, Chronic / Q000097:blood* / Q000188:drug therapy*; D006801:Humans; D007372:Interferons; D007378:Interleukins / Q000097:blood* / Q000494:pharmacology; D019259:Lamivudine / Q000494:pharmacology / Q000627:therapeutic use; D008103:Liver Cirrhosis / Q000097:blood; D008113:Liver Neoplasms / Q000097:blood*; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000494:pharmacology / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D011994:Recombinant Proteins; D000068698:Tenofovir / Q000494:pharmacology / Q000627:therapeutic use; D015854:Up-Regulation / Q000235:genetics; D055815:Young Adult; D000095022:Interferon Lambda
chemical_list: D000225:Adenine; D000998:Antiviral Agents; D017077:Culture Media, Conditioned; D004279:DNA, Viral; D006147:Guanine; D006514:Hepatitis B Surface Antigens; D007372:Interferons; D007378:Interleukins; D019259:Lamivudine; D063065:Organophosphonates; D011994:Recombinant Proteins; D000068698:Tenofovir; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C413685:entecavir; C053001:adefovir
keywords: ANTIVIRAL THERAPY; CHRONIC VIRAL HEPATITIS; INTERFERON