Premium
Differential effects of calcineurin inhibitors, tacrolimus and cyclosporin a, on interferon‐induced antiviral protein in human hepatocyte cells
Author(s) -
Hirano Kumi,
Ichikawa Tatsuki,
Nakao Kazuhiko,
Matsumoto Azusa,
Miyaaki Hisamitsu,
Shibata Hidetaka,
Eguchi Susumu,
Takatsuki Mitsuhisa,
Ikeda Masanori,
Yamasaki Hironori,
Kato Nobuyuki,
Kanematsu Takashi,
Ishii Nobuko,
Eguchi Katsumi
Publication year - 2008
Publication title -
liver transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.814
H-Index - 150
eISSN - 1527-6473
pISSN - 1527-6465
DOI - 10.1002/lt.21358
Subject(s) - calcineurin , phosphorylation , interferon , tyrosine phosphorylation , protein kinase r , janus kinase , hepatocyte , microbiology and biotechnology , jak stat signaling pathway , interferon regulatory factors , biology , stat protein , cancer research , protein kinase a , transcription factor , stat3 , transplantation , virology , medicine , receptor tyrosine kinase , biochemistry , gene , cyclin dependent kinase 2 , in vitro
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‐α‐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‐α‐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‐α combined with Tac attenuated the ISRE‐containing promoter gene activity as compared with IFN‐α alone. In contrast, its expression in pretreated CyA was slightly attenuated. In pretreated Tac, but not CyA, the levels of IFN‐α‐induced tyrosine phosphorylated STAT‐1 and ‐2 were clearly lower than those induced by IFN‐α alone. Tac and CyA did not decrease the IFN‐α‐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‐α. 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 ISRE‐containing 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.