Bile Acids Promote HCV Replication through the EGFR/ERK Pathway in Replicon-Harboring Cells

Objectives: Bile acids promoted the replication of hepatitis C virus (HCV) and compromised the anti-HCV effects of interferon (IFN) in replicon-harboring cells. To explore a potential mechanism for the observation, we studied the effects of bile acids on the epidermal growth factor receptor (EGFR) and the extracellular signal-regulated kinase (ERK) pathway in association with HCV replication in genotype 1a or 1b replicon-harboring cells. Methods: Replicon-harboring cells were treated with various bile acids, IFN and small molecule inhibitors either individually or combined together. The effects of these treatments were measured using cell cycle analysis, qRT-PCR, and Western blot analysis. Results: Bile acids induced the activation of EGFR/ERK pathway and extended S-phase of cells, which was correlated with the increased levels of viral replication. The inhibitors of EGFR (AG1478) or ERK (U0126) significantly mitigated the bile acidmediated promotion of HCV replication. When AG1478 or U0126 were added to the treatment of bile acids and IFN , they were able to restore the anti-HCV effects of IFN . Conclusion: Our data suggest that the addition of an EGFR or ERK Received: February 8, 2010 Accepted after revision: September 20, 2010 Published online: February 5, 2011 Dr. Kyeong-Ok Chang Department of Diagnostic Medicine and Pathobiology College of Veterinary Medicine, Kansas State University 1800 Denison Avenue, Manhattan, KS 66506 (USA) Tel. +1 785 532 3849, Fax +1 785 532 4039, E-Mail kchang @ vet.ksu.edu © 2011 S. Karger AG, Basel Accessible online at: www.karger.com/int D ow nl oa de d by : 54 .7 0. 40 .1 1 11 /4 /2 01 7 6: 10 :2 1 P M