J Hepatol. 2010 Dec 10. [Epub ahead of print]
Zhang L, Jilg N, Shao RX, Lin W, Fusco DN, Zhao H, Goto K, Peng LF, Chen WC, Chung RT.
Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Abstract
BACKGROUND AND AIMS: The combination of pegylated interferon (IFN) α and ribavirin (RBV) is standard therapy for patients with chronic HCV infection. However, it produces a sustained virologic response (SVR) in only half of treated individuals and is associated with significant side effects. Recently several single-nucleotide polymorphisms (SNPs) near the IL28B locus, also known as IFNλ3, were identified to be strong predictors of SVR in patients receiving PEG-IFN and RBV. We sought to determine whether IL28B was capable of inhibiting HCV replication and to determine the pathway by which IL28B exhibits anti-HCV activity.
METHODS: Using the full-length HCV replicon OR6 and the infectious HCV clones JFH1 and Jc1, we assessed the anti-HCV effect of IL28B on HCV and characterized the key steps of the JAK-STAT pathway by real time PCR, luciferase assay, and Western blot. Finally, we evaluated the anti-HCV effect of IL28B in the presence of JAK-STAT pathway inhibitors such as blocking antibodies, a pharmacological inhibitor and siRNAs.
RESULTS: We found that IL28B inhibits HCV replication in a dose- and time- dependent manner. Like IFNα, IL28B induces the phosphorylation of STAT1 and STAT2, ISRE-driven transcription, and expression of known ISGs. The anti-HCV effects of IL28A, IL28B and IL29 were abrogated by an IL10R2 blocking antibody, a pharmacological inhibitor of JAK1/TYK2, and by siRNA against IL28R1, STAT1, STAT2 and IRF9.
CONCLUSIONS: Our data demonstrate that IL28A, IL28B and IL29 signal through the JAK-STAT pathway to inhibit HCV. These data suggest possible applications of new approaches in HCV treatment.
Copyright © 2010. Published by Elsevier B.V.
PMID: 21147189 [PubMed - as supplied by publisher]
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