Interleukin-8 in HepG2 cells: Enhancing antiviral proteins in uninfected cells but promoting HBV replication in infected cells

In vitro studies have revealed that hepatitis B virus (HBV) infection upregulates interleukin-8 (IL-8), which enhances HBV replication. Clinically, elevated IL-8 levels in chronic HBV patients are associated with diminished therapeutic efficacy of interferon-alpha (IFN-alpha). Our study advances these findings by demonstrating that IL-8 promotes the expression of myxovirus resistance A (MxA) and protein kinase R (PKR) in HepG2 cells via the PI3KAKT pathway. However, HBV-infected cells fail to exhibit IL-8-induced upregulation of MxA and PKR, likely due to HBV's upregulation of PP2A that inhibits the PI3K-AKT pathway. Notably, IL-8 targets the C/EBP alpha transcription factor, increasing HBV promoter activity and viral replication, which in turn partially suppresses the expression of MxA and PKR induced by IFN-alpha. Our findings uncover a mechanism by which HBV may evade immune responses, suggesting potential new strategies for immunotherapy against chronic HBV infection.