The premise of our study is that selective inhibition of interferon (IFN) by calcineurin inhibitors contribute to the increased severity of hepatitis C virus (HCV) posttransplantation. Therefore, we examined the influence of calcineurin inhibitors in the human hepatocyte cell line on IFN-␣-induced phosphorylation of Janus kinase (Jak) and signal transducers and activators of transcription (STAT), nuclear translocation of IFN-stimulated gene factor 3 (ISGF-3), IFN-stimulated regulatory element (ISRE)-contained promoter activity, and the expressions of antiviral proteins. Tacrolimus (Tac), but not cyclosporin A (CyA), had an inhibitory effect on IFN-␣-induced double-stranded ribonucleic acid (RNA)-dependent protein kinase (PKR) in a dose-dependent manner. STAT-1 also acted in a similar fashion to PKR. IFN-␣ combined with Tac attenuated the ISREcontaining promoter gene activity as compared with IFN-␣ alone. In contrast, its expression in pretreated CyA was slightly attenuated. In pretreated Tac, but not CyA, the levels of IFN-␣-induced tyrosine phosphorylated STAT-1 and -2 were clearly lower than those induced by IFN-␣ alone. Tac and CyA did not decrease the IFN-␣-induced JAK-1 phosphorylation. The nuclear translocation rate of tyrosine phosphorylated STAT-1 was inhibited by pretreatment of both Tac and CyA by western blotting and immunohistochemistry. In an HCV replicon system, pretreated Tac diminished the replication inhibitory effect of IFN-␣. In this study, we show that calcineurin inhibitors, especially Tac, are the negative regulators of IFN signaling in the hepatocyte; the greatest cause of such inhibition is the phosphorylation disturbance of STAT-1, next to inhibition of the nuclear translocation of STAT-1. In conclusion, disturbance of tyrosine phosphorylation of STAT-1 resulted in diminished ISREcontaining promoter activity and a decline in antiviral protein expression. Moreover, the replication of HCV was activated. This phenomenon is detrimental to IFN therapy after liver transplantation, and the selection of calcineurin inhibitors may warrant further discussion depending on the transplant situation. Liver Transpl 14:292-298, 2008. © 2008 AASLD. Received March 8, 2007 accepted August 17, 2007. See Editorial on Page 265Hepatitis C virus (HCV) infection is widespread worldwide. A major problem of chronic HCV infection is hepatocellular carcinoma. Currently, liver transplantation for HCV-related liver disease is an option worldwide. Recently, it has been demonstrated that the prognosis for liver transplantation patients with HCV-related disease deteriorates with time, 2 resulting in a poorer out-
IFN-induced mTOR activity, independent of PI3K and Akt, is the critical factor for its anti-HCV activity. Jak independent mTOR activity involved STAT-1 phosphorylation and nuclear location, and then PKR is expressed in hepatocytes.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.