Hepatitis C virus core protein subverts the antiviral activities of human Kupffer cells.
OBJECTIVE
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)-1beta, TNF-alpha, and IL-10 and up-regulate cell surface PD-L1. HCVc blocked TLR3-mediated 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 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.
Tu
Zhengkun
Z
Department of Surgery, Division of Solid Organ Transplantation and Hepatobiliary Surgery, University of Rochester Medical Center, Rochester, New York 14642, USA.
Pierce
Robert H
RH
Kurtis
Jonathan
J
Kuroki
Yoshio
Y
Crispe
I Nicholas
IN
Orloff
Mark S
MS
D015703:Antigens, CD / Q000378:metabolism; D060890:B7-H1 Antigen; D002478:Cells, Cultured; D016174:Hepacivirus; D006526:Hepatitis C / Q000276:immunology / Q000378:metabolism* / Q000821:virology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D007728:Kupffer Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology; D014758:Viral Core Proteins / Q000378:metabolism*
D015703:Antigens, CD; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C508609:IL10 protein, human; D053583:Interleukin-1beta; C495342:TLR2 protein, human; C495344:TLR3 protein, human; C495345:TLR4 protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; D016753:Interleukin-10; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases