|
- 现金
- 62111 元
- 精华
- 26
- 帖子
- 30437
- 注册时间
- 2009-10-5
- 最后登录
- 2022-12-28
|
614
Induction of IFN-λ3 as an Additional Effect of Nucleotide,
Not Nucleoside, Analogs: A New Potential Target
for Hepatitis B Virus Infection
Kazumoto Murata1, Akihiro Matsumoto2, Masaya Sugiyama1, Eiji
Tanaka2, Taisuke Inoue3, Minoru Sakamoto3, Nobuyuki Enomoto3,
Masao Honda4, Shuichi Kaneko4, Hiroyuki Gatanaga5, Shinichi
Oka5, Masashi Mizokami1; 1The Research Center for Hepatitis and
Immunology, National Center for Global Health and Medicine,
Tokyo, Japan; 2Shinshu University School of Medicine, Matsumoto,
Japan; 3University of Yamanashi, Chuo, Japan; 4kanazawa University,
Kanazawa, Japan; 5National Center for Global Health
and Medicine, Tokyo, Japan
BACKGROUND & AIM: Interferon (IFN)-λ3 is known to directly
inhibit replication of several kinds of viruses including HBV,
and induce IFN-stimulated genes (ISGs). In chronic hepatitis
C, interleukin (IL)-28B, encoding IFN-λ3, was identified as a
significant factor for favorable response to pegylated-IFN/ribavirin
by genome-wide association study. However, its clinical
significance in hepatitis B virus (HBV) infection is still elusive.
Our aim of this study is to investigate clinical roles of IFN-λ3
in HBV patients and its association with nucleos(t)ide analog
(NUC) treatment . METHODS: Using our newly-developed chemiluminescence
enzyme immunoassay for IFN-λ3 that show
high sensitivity and high specificity, serum IFN-λ3 levels were
measured in a total of 254 HBV patients (asymptomatic carriers;
n=83, chronic hepatitis; n=103, liver cirrhosis; n=25,
hepatocellularcarcinoma; n=43) treated with or without NUCs,
and compared with their clinical backgrounds. Serum IFN-λ3
levels during treatment with NUC were also measured using
series of samples for each patient. mRNA and protein levels of
IFN-λ3 were measured in vitro by treating several cell lines from
different origins with NUC. Levels of ISGs (MX1 and OAS2),
or HBsAg in hepatoma cells was examined following stimulation
with supernatant from adefovir pivoxil (ADV)- or entecavir
(ETV)-treated colon cancer cells. RESULTS: Higher serum IFN-λ3
levels were measured in HBV patients treated with nucleotide
analogs (ADV, tenofovir disoproxil fumarate; TDF) compared
with those treated with nucleoside analogs (lamivudine; LAM,
ETV), or treatment, with no differences in their clinical backgrounds.
Serum IFN-λ3 levels were increased after initiation
of nucleotide analogs, and not nucleoside analogs. In vitro
experiments showed that nucleotide analogs directly and
dose-dependently induced IFN-λ3 production only in colon cancer
cells among cells tested, which was confirmed by mRNA
up-regulation and positive immunohistochemical staining. In
addition, supernatants from ADV-treated colon cancer cells significantly
up-regulated MX1 and OAS2, and inhibited HBsAg
production in hepatoma cells, compared with ETV-treated cells.
Conclusions: We provide the first demonstration that nucleotide
analogs, and not nucleoside analogs, have an additional
pharmacological effect of inducing IFN-λ3, followed by ISG
induction, which both contribute to HBsAg reduction. This
would have a significant clinical impact for anti-HBV effects in
the liver because IFN-λ3 induced in the gastrointestinal tracts
enters the liver via the portal vein. Therefore, this mechanistic
link might provide novel insights and potential targets for anti-
HBV treatment.
Disclosures:
Shuichi Kaneko - Grant/Research Support: MDS, Co., Inc, Chugai Pharma., Co.,
Inc, Toray Co., Inc, Daiichi Sankyo., Co., Inc, Dainippon Sumitomo, Co., Inc,
Ajinomoto Co., Inc, Bristol Myers Squibb., Inc, Pfizer., Co., Inc, Astellas., Inc,
Takeda., Co., Inc, Otsuka„ÄÄPharmaceutical, Co., Inc, Eizai Co., Inc, Bayer
Japan, Eli lilly Japan
The following people have nothing to disclose: Kazumoto Murata, Akihiro Matsumoto,
Masaya Sugiyama, Eiji Tanaka, Taisuke Inoue, Minoru Sakamoto,
Nobuyuki Enomoto, Masao Honda, Hiroyuki Gatanaga, Shinichi Oka, Masashi
Mizokami
|
|
发表于 2016-10-19 15:53
