Hepatitis C Virus Core and Nonstructural Protein 3 Proteins Induce Pro- and Anti-inflammatory Cytokines and Inhibit Dendritic Cell Differentiation

Abstract

Antiviral immunity requires recognition of viral pathogens and activation of cytotoxic and Th cells by innate immune cells. In this study, we demonstrate that hepatitis C virus (HCV) core and nonstructural protein 3 (NS3), but not envelope 2 proteins (E2), activate monocytes and myeloid dendritic cells (DCs) and partially reproduce abnormalities found in chronic HCV infection. HCV core or NS3 (not E2) triggered inflammatory cytokine mRNA and TNF-α production in monocytes. Degradation of I-κBα suggested involvement of NF-κB activation. HCV core and NS3 induced production of the anti-inflammatory cytokine, IL-10. Both monocyte TNF-α and IL-10 levels were higher upon HCV core and NS3 protein stimulation in HCV-infected patients than in normals. HCV core and NS3 (not E2) inhibited differentiation and allostimulatory capacity of immature DCs similar to defects in HCV infection. This was associated with elevated IL-10 and decreased IL-2 levels during T cell proliferation. Increased IL-10 was produced by HCV patients’ DCs and by core- or NS3-treated normal DCs, while IL-12 was decreased only in HCV DCs. Addition of anti-IL-10 Ab, not IL-12, ameliorated T cell proliferation with HCV core- or NS3-treated DCs. Reduced allostimulatory capacity in HCV core- and NS3-treated immature DCs, but not in DCs of HCV patients, was reversed by LPS maturation, suggesting more complex DC defects in vivo than those mediated by core or NS3 proteins. Our results reveal that HCV core and NS3 proteins activate monocytes and inhibit DC differentiation in the absence of the intact virus and mediate some of the immunoinhibitory effects of HCV via IL-10 induction.

Peripheral virus-specific T-cell interleukin-10 responses develop early in acute hepatitis C infection and become dominant in chronic hepatitis

“…IL-10 is produced by many cell types including dendritic cells (28,29), macrophages, monocytes, NK (30,31) and NKT-cells (32) with pleiotropic effects. For example, IL-10 can downregulate antigen processing by transporter-associated with antigen processing, MHC expression and IL-12 production by antigen-presenting cells (APC) (9,10), resulting in impaired T-cell proliferation, effector function and memory (33).…”

Human herpesvirus 6 infection in adult living related liver transplant recipients

“…It has been shown that TNF-␣ synthesis is up-regulated in patients with HCV chronic hepatitis. 43,44 As inflammatory cytokines including TNF-␣ have been suggested to trigger HHV-6 reactivation, 30 it is possible that HHV-6 replication might increase in HCV carriers. In addition, Rogers et al 7 demonstrated that patients infected with HHV-6 are more likely to have hepatocellular carcinoma as an underlying disease; however, they also found that the frequency of HHV-6 infection was not different between HBV and/or HCV carriers and noncarriers.…”

Increased natural cytotoxicity receptor expression and relevant IL‐10 production in NK cells from chronically infected viremic HCV patients

“…With respect to an involvement of innate immune responses in HCV-infected patients, so far there is contrasting evidence of either normal or reduced numbers or function of circulating myeloid or plasmacytoid DC [29][30][31][32]. Additional suggestion of the involvement of innate immune mechanism(s) in the establishment of chronic HCV infection derive from the description of NK cell dysfunction (inhibition) following CD16-mediated triggering when CD81 molecules on NK cells are bound to HCV E2 protein [33].…”

“…During Mycobacterium tuberculosis infection in vitro, NK cells control pathogen replication in monocytes via natural cytotoxicity receptor (NCR) killing [21], and removal of NK cells from the peripheral blood of patients with latent tuberculosis significantly reduces mycobacterium-specific CD8 + CTL function [22]. Similarly, the dysfunction of NK cells observed during HIV-1 infection [23,24] has been recently associated with decreased expression of the major NCR (NKp30, NKp46 and NKp44), with a significant level of peripheral NK cell activation and inefficient lysis of HIVinfected CD4 + T cells [25][26][27][28].With respect to an involvement of innate immune responses in HCV-infected patients, so far there is contrasting evidence of either normal or reduced numbers or function of circulating myeloid or plasmacytoid DC [29][30][31][32]. Additional suggestion of the involvement of innate immune mechanism(s) in the establishment of chronic HCV infection derive from the description of NK cell dysfunction (inhibition) following CD16-mediated triggering when CD81 molecules on NK cells are bound to HCV E2 protein [33].…”