https://scholars.lib.ntu.edu.tw/handle/123456789/332977
Title: | Ribavirin up-regulates the activity of double-stranded RNA-activated protein kinase and enhances the action of interferon-α against hepatitis C virus | Authors: | Liu W.-L. Su W.-C. Cheng C.-W. Hwang L.-H. Wang C.-C. Chen H.-L. DING-SHINN CHEN Lai M.-Y. |
Issue Date: | 2007 | Journal Volume: | 196 | Journal Issue: | 3 | Start page/Pages: | 425-434 | Source: | Journal of Infectious Diseases | Abstract: | Background. Ribavirin's mechanism of action in the treatment of chronic hepatitis C remains to be clarified. Double-stranded RNA-activated protein kinase (PKR) plays a role in cell defense against virus infection. This study investigated whether PKR is a mediator of the effectiveness of ribavirin, used either alone or in combination with interferon (IFN)-α, against hepatitis C virus (HCV) infection. Methods. Primary human hepatocytes and HCV-replicon cells were treated with ribavirin and/or IFN-α. PKR activity was assayed by immunoblotting. A pulse-chase assay of the half-life of PKR protein was performed to study whether ribavirin decreases PKR degradation. We used small-interference RNA (siRNA) to knock down PKR to assess its importance in the suppression of HCV-RNA replication in the replicon system. Results. Ribavirin was able to up-regulate the levels of phosphorylated PKR and phosphorylated eIF2α, leading to suppression of HCV-RNA replication. The effects that treatment with ribavirin plus IFN-α had on PKR activity were greater than those observed for treatment with either ribavirin alone or IFN-α alone. Knockdown of PKR increased HCV-RNA replication, supporting the importance of PKR in the control of HCV-RNA replication. The pulse-chase experiment showed that ribavirin can reduce the degradation rate of PKR protein. Conclusion. These results suggest that the anti-HCV action of ribavirin is partly attributable to its ability to up-regulate PKR activity. ? 2007 by the Infectious Diseases Society of America. All rights reserved. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-34447618973&doi=10.1086%2f518894&partnerID=40&md5=1a8d9517c3b2d39a3b38ec4635f36deb http://scholars.lib.ntu.edu.tw/handle/123456789/332977 |
DOI: | 10.1086/518894 | SDG/Keyword: | alpha interferon; initiation factor 2alpha; protein kinase R; ribavirin; small interfering RNA; article; controlled study; drug mechanism; hepatitis C; human; human cell; immunoblotting; liver cell; priority journal; protein degradation; protein phosphorylation; replicon; virus replication; Antiviral Agents; Cells, Cultured; Drug Therapy, Combination; eIF-2 Kinase; Gene Expression Regulation, Enzymologic; Hepacivirus; Humans; Interferon-alpha; Ribavirin; RNA, Viral; Up-Regulation; Virus Replication |
Appears in Collections: | 醫學系 |
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