Hepatitis C virus core protein activates ERK and p38 MAPK in cooperation with ethanol in transgenic mice

In human chronic hepatitis C, alcohol intake is a synergistic factor for the acceleration of hepatocarcinogenesis. Recently, we showed a significant increase of reactive oxygen species (ROS) in hepatitis C virus (HCV) core‐transgenic mice fed ethanol‐containing diets. Because previous studies indicated that ROS is closely associated with mitogen‐activated protein kinases (MAPK), we examined activities of c‐Jun N‐terminal kinase, p38 MAPK, and extracellular signal‐regulated kinase (ERK) in the liver of core‐transgenic and nontransgenic mice with short‐term ethanol feeding. Activity of ERK and p38 MAPK was increased in core‐transgenic mice compared with nontransgenic mice, whereas neither ERK nor p38 MAPK was activated in core‐transgenic mice with normal diets. In addition, activity of cyclic‐AMP and serum responsive element, downstream pathways of p38 MAPK and ERK, was also increased. Comparison of gene expression profiles by cDNA microarray and real‐time PCR revealed that galectin‐1, which is associated with cell transformation, was significantly increased in ethanol‐fed core‐transgenic mice. On the other hand, glutathione S‐transferase (GST), which plays a key role in protecting cells from oxidative stress, was decreased. In conclusion, these results suggest that HCV core protein cooperates with ethanol for the activation of some MAPK pathways, and leads to the modulation of several genes, contributing to the pathogenesis of liver disease of HCV‐ infected patients with high ethanol consumption. (Hepatology 2003;38:820–828).