The hepatitis C virus core protein indirectly induces alpha-smooth muscle actin expression in hepatic stellate cells via interleukin-8

Background & Aims

Progressive deposition of liver fibrosis is a common feature of chronic hepatitis associated with hepatitis C virus (HCV) infection, and it may eventually lead to cirrhosis and liver failure. Although this fibrogenic process appears to be linked to HCV protein expression and replication via indirect mechanisms, i.e., to be mediated by virally-driven inflammation, a direct role of HCV in inducing fibrosis deposition has never been entirely excluded.

Methods

We established an in vitro system in which the human hepatic stellate cell line LX-2 was cultured in the presence of conditioned medium from human hepatoma Huh-7 cells transduced with a lentiviral vector expressing HCV core proteins of different genotypes.

Results

Treatment of LX-2 cells, with conditioned medium from Huh-7 cells expressing HCV core protein, led to the activation of α-smooth muscle actin expression. Among the chemokines secreted by cells transduced with HCV core, interleukin-8 was identified as the strongest inducer of α-smooth muscle actin expression in LX-2 and primary hepatic stellate cells. This effect was accompanied by a decrease in cell migration and increased focal contact organisation.

Conclusions

The expression of the HCV core in hepatocytes may contribute to the establishment of a profibrogenic microenvironment.

Abbreviations: HCV, hepatitis C virus, HSC, hepatic stellate cells, IL-8, interleukin-8, PCR, polymerase chain reaction, EF1, elongation factor 1, EGFP, empty and green fluorescent protein, SMA, smooth muscle actin, FCS, foetal calf serum, CM, conditioned medium, SD, standard deviation, MMP2, matrix metalloproteinase 2, TIMP1, tissue inhibitor of metalloproteinase 1, CTGF, connective tissue growth factor, EMT, epithelial to mesenchymal transition

Keywords: Liver fibrosis, Cytokines, Hepatitis C