Hepatitis C Virus Core Protein Subverts the Antiviral Activities of Human Kupffer Cells

BACKGROUND & AIMS: Kupffer cells (KC) are important innate immune cells of the liver, functioning as scavenging sinusoidal phagocytes and transducers of pattern recognition signals, including those of roll-like receptors (TLRs). The hepatitis C virus core protein (HCVc) engages TLR2 on peripheral blood monocytes and induces production of multiple inflammatory cytokines. We examined the effects of HCVc oil primary KC functions. METHODS: KC were isolated From living donor allografts and stimulated with HCVc and/or ligands for TLRs. KC were examined for production of cytokines, expression of programmed death-ligand I (PD-L1) secretion of type I interferons (IFNs),and expression of the apoptosis-inducing protein tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). RESULTS: HCVc acts as a ligand for TLR2 oil human KC, inducing them to secrete interleukin (IL)-1 beta, TNF-alpha, and IL-10 and up-regulate cell surface PD-L1. HCVc blocked TLR3-mediaced secretion of IFN-alpha, IFN-beta, and Cell Surface expression of the cytotoxic molecule TRAIL. Inhibition of phosphoinositide 3 kinase with LY294002 blocked the Up-regulation of PD-L1. by TLR ligands and the TLR3-specific induction of TRAIL and type I IFNs. CONCLUSIONS: KC are intravascular macrophages that are continuously exposed to, and tolerant of, bacterial TLR ligands, which are delivered via the portal circulation. By mimicking a bacterial TLR2 ligand and effectively blocking the TLR3-mediated, double-stranded RNA-induced antiviral response, HCVc might appear to exploit this unique aspect of immunity in the liver.