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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
Kazumoto Murata1, Mai Asano1,2, Akihiro Matsumoto3, Masaya Sugiyama1, Nao Nishida1, Eiji Tanaka3, Taisuke Inoue4, Minoru Sakamoto4, Nobuyuki Enomoto4, Takayoshi Shirasaki5, Masao Honda5, Shuichi Kaneko5, Hiroyuki Gatanaga6, Shinichi Oka6, Yuki I Kawamura7, Taeko Dohi7, Yasutaka Shuno8, Hideaki Yano8, Masashi Mizokami1,2
Author affiliations
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
Department of Medicine, Shinshu University of Medicine, Matsumoto, Japan
First Department of Medicine, University of Yamanashi, Chuo, Japan
Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan
Department of Gastroenterology, The Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Ichikawa, Japan
Division of Colorectal Surgery, Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan
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; [email protected]
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.
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/
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http://dx.doi.org/10.1136/gutjnl-2016-312653
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发表于 2018-1-9 20:45
