Hepatitis C Virus mediates induction of CXC chemokine expression in response to the inflammatory cytokines TNFα and IL-1β

Background & aims:

HCV has evolved powerful mechanisms to manipulate antiviral and innate immunity and to interfere with the inflammatory host response. Thereby the local composition of inflammatory and immune cells is largely determined by the pattern of chemokines released from the different cell types of the liver. We could recently demonstrate that HCV enhances basal and EGF-dependent expression of the chemokines CXCL1, 2, 3 and 8 (Groepper et al., 2018). The present study investigates the influence of HCV on inducible expression of these chemokines in response to the inflammatory cytokines TNFα and IL-1β either alone or in combination.

Methods:

Huh-7 cells either infected with the HCVcc strain JC1 or harbouring the HCV subgenomic replicon were used to analyse the impact of HCV on cellular signalling and inducible chemokine expression in response to TNFα and IL-1β.

Results:

HCV activates key enzymes of the PI3K/Akt signalling pathway in response to TNFα as well as IL-1β and enhances TNFα- and IL-1β-inducible CXCR2 ligand expression. Additionally, TNFα- and IL-1β display synergistic effects in the upregulation of CXCR2 ligands during HCV infection.

Conclusions:

HCV executes altered activation of key enzymes of the PI3K/Akt signalling pathway in response to TNFα and IL-1β. These alterations are even more dominant in infected cells treated with TNFα. In response to the inflammatory cytokines TNFα and IL-1β, the expression of the CXCR2 ligands CXCL1, 2, 3 and 8 is enhanced in HCV-infected cells compared to uninfected cells. Furthermore, TNFα and IL-1β reveal synergistic effects on the elevation of CXCR2 ligand expression.