Article Text
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
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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.