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

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 associati...

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Autores principales: Murata, Kazumoto, Asano, Mai, Matsumoto, Akihiro, Sugiyama, Masaya, Nishida, Nao, Tanaka, Eiji, Inoue, Taisuke, Sakamoto, Minoru, Enomoto, Nobuyuki, Shirasaki, Takayoshi, Honda, Masao, Kaneko, Shuichi, Gatanaga, Hiroyuki, Oka, Shinichi, Kawamura, Yuki I, Dohi, Taeko, Shuno, Yasutaka, Yano, Hideaki, Mizokami, Masashi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868296/
https://www.ncbi.nlm.nih.gov/pubmed/27789659
http://dx.doi.org/10.1136/gutjnl-2016-312653
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author Murata, Kazumoto
Asano, Mai
Matsumoto, Akihiro
Sugiyama, Masaya
Nishida, Nao
Tanaka, Eiji
Inoue, Taisuke
Sakamoto, Minoru
Enomoto, Nobuyuki
Shirasaki, Takayoshi
Honda, Masao
Kaneko, Shuichi
Gatanaga, Hiroyuki
Oka, Shinichi
Kawamura, Yuki I
Dohi, Taeko
Shuno, Yasutaka
Yano, Hideaki
Mizokami, Masashi
author_facet Murata, Kazumoto
Asano, Mai
Matsumoto, Akihiro
Sugiyama, Masaya
Nishida, Nao
Tanaka, Eiji
Inoue, Taisuke
Sakamoto, Minoru
Enomoto, Nobuyuki
Shirasaki, Takayoshi
Honda, Masao
Kaneko, Shuichi
Gatanaga, Hiroyuki
Oka, Shinichi
Kawamura, Yuki I
Dohi, Taeko
Shuno, Yasutaka
Yano, Hideaki
Mizokami, Masashi
author_sort Murata, Kazumoto
collection PubMed
description 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.
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spelling pubmed-58682962018-03-27 Induction of IFN-λ3 as an additional effect of nucleotide, not nucleoside, analogues: a new potential target for HBV infection Murata, Kazumoto Asano, Mai Matsumoto, Akihiro Sugiyama, Masaya Nishida, Nao Tanaka, Eiji Inoue, Taisuke Sakamoto, Minoru Enomoto, Nobuyuki Shirasaki, Takayoshi Honda, Masao Kaneko, Shuichi Gatanaga, Hiroyuki Oka, Shinichi Kawamura, Yuki I Dohi, Taeko Shuno, Yasutaka Yano, Hideaki Mizokami, Masashi Gut Hepatology 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. BMJ Publishing Group 2018-02 2016-10-27 /pmc/articles/PMC5868296/ /pubmed/27789659 http://dx.doi.org/10.1136/gutjnl-2016-312653 Text en Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/ 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/
spellingShingle Hepatology
Murata, Kazumoto
Asano, Mai
Matsumoto, Akihiro
Sugiyama, Masaya
Nishida, Nao
Tanaka, Eiji
Inoue, Taisuke
Sakamoto, Minoru
Enomoto, Nobuyuki
Shirasaki, Takayoshi
Honda, Masao
Kaneko, Shuichi
Gatanaga, Hiroyuki
Oka, Shinichi
Kawamura, Yuki I
Dohi, Taeko
Shuno, Yasutaka
Yano, Hideaki
Mizokami, Masashi
Induction of IFN-λ3 as an additional effect of nucleotide, not nucleoside, analogues: a new potential target for HBV infection
title Induction of IFN-λ3 as an additional effect of nucleotide, not nucleoside, analogues: a new potential target for HBV infection
title_full Induction of IFN-λ3 as an additional effect of nucleotide, not nucleoside, analogues: a new potential target for HBV infection
title_fullStr Induction of IFN-λ3 as an additional effect of nucleotide, not nucleoside, analogues: a new potential target for HBV infection
title_full_unstemmed Induction of IFN-λ3 as an additional effect of nucleotide, not nucleoside, analogues: a new potential target for HBV infection
title_short Induction of IFN-λ3 as an additional effect of nucleotide, not nucleoside, analogues: a new potential target for HBV infection
title_sort induction of ifn-λ3 as an additional effect of nucleotide, not nucleoside, analogues: a new potential target for hbv infection
topic Hepatology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868296/
https://www.ncbi.nlm.nih.gov/pubmed/27789659
http://dx.doi.org/10.1136/gutjnl-2016-312653
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