Hepatitis C Virus EGF-dependently induces the release of CXCR2 ligands and enhances their EGF-inducible release via distinct pathways

Background & aims:

The Hepatitis C Virus influences the immune response by interaction of viral proteins with cellular signalling intermediates. Thereby, apart from others, it also affects the recruitment of several immune cells resulting in an alteration of the inflammatory microenvironment of its host cell. However, the underlying molecular mechasnisms are only incompletely understood. Aim of the present study was to further characterize the mechanisms by which HCV modifies the release of intercellular communication signals from its host cell.

Methods:

Chemokine expression was measured in cells infected with HCV or in cell lines harbouring the subgenomic replicon as well as in serum samples from patients chronically infected with HCV or from respective controls. Furthermore, chemokine expression was determined after addition of small interfering RNA (siRNA) or specific inhibitors of key enzymes.

Results:

Evidence is provided that HCV enhances basal CXCR2 ligand expression via an EGF driven circuit. Consistently knock down of EGF expression by specific siRNA almost completely abrogates upregulation of CXCR ligand expression by HCV. Additionally, HCV reduces expression levels of the T-cell protein tyrosine phosphatase (TC-PTP), which results in an enhanced activation of EGFR downstream signalling via activation of MEK1 and Akt. This enhanced activation is required to mediate the HCV-dependent enhancement of EGF-inducible CXCR ligand expression, which chemokine-dependently involves activation of Akt or MEK1. Thereby activation of Akt is required to mediate expression of the CXCR2 ligands CXCL1, 2 and 3 but not of CXCL8, while CXCL8 expression depends on activation of MEK1. In line with these observations serum levels of EGF and the CXCR2 ligand CXCL8 are increased in patients suffering from chronic HCV infection when compared to respective controls.

Conclusions:

This study provides novel evidence that HCV entails an interconnection between EGF signalling and regulation of CXCR2 ligand expression, which chemokine-dependently involves distinct pathways.