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

Tu, Zhengkun; Pierce, Robert H.; Kurtis, Jonathan; Kuroki, Yoshio; Crispe, I. Nicholas; Orloff, Mark S.

doi:10.1053/j.gastro.2009.09.009

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Volume 138, Issue 1 , Pages 305-314, January 2010

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

Zhengkun Tu
- Department of Surgery, Division of Solid Organ Transplantation and Hepatobiliary Surgery, University of Rochester Medical Center, Rochester, New York
Robert H. Pierce
- Department of Pathology, Schering-Plough Biopharma, Palo Alto, California
Jonathan Kurtis
- Center for International Health Research, Department of Pathology and Laboratory Medicine, Rhode Island Hospital, Brown University, Providence, Rhode Island
Yoshio Kuroki
- Department of Biochemistry, Sapporo Medical University School of Medicine, Sapporo, Japan
I. Nicholas Crispe
- Seattle Biomedical Research Institute, Seattle, Washington
Mark S. Orloff
- Department of Surgery, Division of Solid Organ Transplantation and Hepatobiliary Surgery, University of Rochester Medical Center, Rochester, New York
- Reprint requests Address requests for reprints to: Mark S. Orloff, MD, University of Rochester Medical Center, Solid Organ Transplantation and Hepatobiliary Surgery, 601 Elmwood Avenue, Rochester, New York 14642. fax: (585) 276-0054

Received 3 October 2008; accepted 11 September 2009. published online 22 September 2009.

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.

Abbreviations used in this paper: HCV, hepatitis C virus, HCVc, hepatitis C virus core protein, LTA, lipoteichoic acid, MyD88, myeloid differentiation factor 88, pDC, plasmacytoid dendritic cells, PD-1, programmed death-1, PD-L1, programmed death ligand 1, PI3K, phosphoinositide 3-kinase, poly-I:C, polyinosinic:polycytidylic acid, TLR, toll-like receptors, TNF, tumor necrosis factor, TRAIL, TNF-related apoptosis inducing ligand, TRIF, toll-interleukin 1 receptor-domain-containing adaptor-inducing interferon