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JAK inhibitor tofacitinib interferes with interferon alpha mediated inhibition of hepatitis C replication

Ruiter, P.E. de, Baan, C.C., Pan, Q., Kwekkeboom, J., Metselaar, H.J., Bruin, R.W.F. de, Tilanus, H.W., Laan, L.J.W. van der

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Background End stage liver disease caused by chronic hepatitis C infection is a leading indication for liver transplantation. After transplantation however, reinfection of the graft occurs universally, leading to accelerated fibrosis and early development of cirrhosis. The use of immunosuppressive medication after transplantation may contribute to the aggravated course of infection and increased resistance to antiviral therapy. Therefore, there is a need for new immunosuppressive agents. Tofacitinib is a new immunosuppressant that was developed as a selective inhibitor of the Janus kinase 3 (JAK3) but may inhibit other members of the JAK family. Therefore, the aim of our research is to investigate the effect of tofacitinib on HCV replication and JAK1 mediated interferon-α (IFN-α) signalling. 

 
Methods As a model for HCV replication we used a Huh7 hepatoma cell line, stably transfected with the non-structural coding sequence of HCV coupled to a luciferase reporter (Huh7-ET). The amount of luciferase in these cells is a direct representation of HCV replication. A Huh7 cell line stably transfected with a luciferase gene controlled by an interferon response element (Huh7-ISRE-luc) was used to investigate effects of tofacitinib on IFN-α signal transduction. 
 
Results In Huh7-ISRE-luc cells, tofacitinib inhibited IFN-α stimulated gene expression in a dose dependent manner. The highest dose of tofacitinib (1000 ng/ml) completely inhibited IFN-α stimulated gene expression and 100 ng/ml tofacitinib reduced IFN-α activity by 50%. With 10 U/ml IFN-α a complete inhibition of HCV replication was observed. This IFN-α mediated inhibition of HCV was completely abrogated by tofacitinib in a dose dependent manner.
 
Conclusion Although tofacitinib was developed as a specific inhibitor of JAK3, with a reported 100-fold less potency for JAK1, we found that tofacitinib effectively inhibits IFN-α regulated gene expression, and interferes with IFN-α mediated inhibition of HCV replication. This observation explains the higher incidence of viral infections found in patients that are treated with tofacitinib.