Effects of corticosteroids on interferon-
α signaling and inhibition of hepatitis C infection by plasmacytoid dendritic cells
P. E. de Ruiter, P.P.C. Boor, Q. Pan, J. de Jonge, H.J. Metselaar, G. Kazemier, H.W.
Tilanus, J. Kwekkeboom, L.J.W. van der Laan
Departments of Surgery and Gastroenterology & Hepatology, Erasmus MC-University Medical Center,
Rotterdam, the Netherlands
Background/aims : Chronic hepatitis C virus (HCV) infection is one of the leading indications for liver transplantation, but outcomes are often compromised by reinfection of the graft. Several studies have indicated that the use of corticosteroidbased immunosuppression is a risk factor for severe HCV recurrence. The mechanism for the steroid-mediated effect on HCV is not fully elucidated, but recent studies using in vitro HCV models found no direct effect on viral replication. The success rate of interferon-

(IFN-
α) based antiviral therapy is significantly lower posttransplantation than in the non-transplant HCV population; however the impact of steroids on the antiviral activity of IFNα is unknown. Therefore, the aim of this study is to investigate the effect of steroids on the antiviral activity of IFN-
α and the impact on the primary IFNα-producing cells, the plasmacytoid dendritic cells (pDCs).
Methods : As a model for HCV replication we used the Huh7 hepatoma cell line, stably transfected with the non-structural coding sequence of HCV directly coupled to a luciferase reporter gene (Huh7-ET), and treated with IFNα in the presence or absence of different doses of prednisolone or dexamethasone. A Huh7 cell line stably transfected with a luciferase gene under the control of an interferon response element (Huh7-ISRE-Luc) was used to assess effects on IFN-
α signal transduction.
To investigate the effects of steroids on pDCs, Huh7-ET cells were co-cultured with pDCs in the presence or absence of steroids, and conditioned media of cultured pDCs were collected.
Results : HCV replication was inhibited by 10 IU/ml IFNα by more than 99% of control levels. Treatment with increasing doses of dexamethasone or prednisolone did not significantly affect HCV replication. When combining IFN-
α with dexamethasone or prednisolone, no interference with the inhibition of HCV replication by IFNα was observed. Moreover, dexamethasone and prednisolone had no effect on IFN-
α signal transduction as measured in Huh7-ISRE-Luc cells.
However, when Huh7-ET cells were co-cultured with pDCs, a significant reduction of
HCV replication was observed, which was almost completely reversed by treatment with steroids. HCV replication in Huh7-ET cells was inhibited by conditioned medium from cultured pDCs, but no inhibition was observed with medium from pDCs that were cultured in de presence of corticosteroids.
In conclusion : We found no evidence that corticosteroids interfere with signal transduction and antiviral action of IFN-
α. However, steroids may affect HCV replication post-transplantation by reducing the antiviral capacity of pDCs.