Hepatitis C virus core protein subverts the antiviral activities of human Kupffer cells
Z Tu, RH Pierce, J Kurtis, Y Kuroki, IN Crispe, MS Orloff - Gastroenterology, 2010 - Elsevier
Z Tu, RH Pierce, J Kurtis, Y Kuroki, IN Crispe, MS Orloff
Gastroenterology, 2010•ElsevierBACKGROUND & 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 toll-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 on human primary KC functions.
METHODS: KC were isolated from living donor allografts and stimulated with HCVc and/or …
functioning as scavenging sinusoidal phagocytes and transducers of pattern recognition
signals, including those of toll-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 on human primary KC functions.
METHODS: KC were isolated from living donor allografts and stimulated with HCVc and/or …
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 toll-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 on human 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 1 (PD-L1), secretion of type 1 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 on human KC, inducing them to secrete interleukin (IL)-1β, TNF-α, and IL-10 and up-regulate cell surface PD-L1. HCVc blocked TLR3-mediated secretion of IFN-α, IFN-β, 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 1 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.
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