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  • Induction of IFN-λ3 as an additional effect of nucleotide, not nucleoside, analogues: a new potential target for HBV infection

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Hepatology
Original article
Induction of IFN-λ3 as an additional effect of nucleotide, not nucleoside, analogues: a new potential target for HBV infection
  1. Kazumoto Murata1,
  2. Mai Asano1,2,
  3. Akihiro Matsumoto3,
  4. Masaya Sugiyama1,
  5. Nao Nishida1,
  6. Eiji Tanaka3,
  7. Taisuke Inoue4,
  8. Minoru Sakamoto4,
  9. Nobuyuki Enomoto4,
  10. Takayoshi Shirasaki5,
  11. Masao Honda5,
  12. Shuichi Kaneko5,
  13. Hiroyuki Gatanaga6,
  14. Shinichi Oka6,
  15. Yuki I Kawamura7,
  16. Taeko Dohi7,
  17. Yasutaka Shuno8,
  18. Hideaki Yano8,
  19. Masashi Mizokami1,2
  1. 1 The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
  2. 2 Department of Hepatitis and Immunology, Nagoya City University Graduate School of Medical Science, Nagoya, Japan
  3. 3 Department of Medicine, Shinshu University of Medicine, Matsumoto, Japan
  4. 4 First Department of Medicine, University of Yamanashi, Chuo, Japan
  5. 5 Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
  6. 6 AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan
  7. 7 Department of Gastroenterology, The Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Ichikawa, Japan
  8. 8 Division of Colorectal Surgery, Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan
  1. Correspondence to Dr Masashi Mizokami, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa 272-8516, Japan; mmizokami{at}hospk.ncgm.go.jp

Abstract

Objective 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.

Design 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.

Results 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.

Conclusions 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.

  • CHRONIC VIRAL HEPATITIS
  • INTERFERON
  • ANTIVIRAL THERAPY

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/gutjnl-2016-312653

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    Footnotes

    • KM and MA contributed equally.

    • Contributors KM and MM conceived and designed the experiments. AM, ET, TI, MS, NE, MH, SK, HG, SO, YS and HY collected patient samples and performed the analyses. KM, MA, MS, NN, TS, MH, YIK and TD performed the experiments. KM and MM wrote the manuscript.

    • Funding This study was supported by the National Center for Global Health and Medicine in Japan (27-1302), Grants-in-Aid for Scientific Research (23390117), and Japan Agency for Medical Research and Development (15fk0210035h0001).

    • Competing interests None declared.

    • Patient consent Obtained.

    • Ethics approval Local Ethics Committee at each associated institute (reference number NCGM-A-000208-0).

    • Provenance and peer review Not commissioned; externally peer reviewed.