Downregulation of Interleukin-18-Mediated Cell Signaling and Interferon Gamma Expression by the Hepatitis B Virus e Antigen

Abstract

The mechanisms by which hepatitis B virus (HBV) establishes and maintains chronic hepatitis B infection (CHBT he mechanisms by which hepatitis B virus (HBV) establishes and maintains persistent infection are not fully understood. It has become increasingly apparent that innate immune response via the effector functions of a range of cell types, including Kupffer cells, natural killer (NK) cells, and hepatocytes, play an important role in controlling HBV infection (1-3). Our group has previously shown that stimulation of the interleukin-1 (IL-1) and toll-like receptor 2 (TLR2) signaling pathways inhibits HBV replication in vitro (4). In turn, we and others have shown that the hepatitis B e antigen (HBeAg; p17) downregulates antiviral TLR2-and IL-1␤-mediated responses (5-7). HBeAg is secreted as a nonparticulate form of the hepatitis B virus (HBV) nucleocapsid protein (hepatitis B core antigen [HBcAg]; p21), which is processed from larger precore polyproteins (p25 and p22) (8). Although not required for HBV replication, the precore protein and HBeAg are critical for the establishment of persistent infection. The HBV precore protein and HBeAg are important regulators of innate and adaptive immune responses that contribute to the establishment and/or maintenance of persistent infection.IL-18 is a proinflammatory cytokine synthesized and secreted by mononuclear cells, including Kupffer cells. In the presence of the necessary costimulatory ligands, such as IL-12 (9), IL-18 stimulates IFN-␥ production by NK cells, T cells, dendritic cells (DCs), and B cells. IL-18 signaling is activated following the interaction of two receptors: the alpha-receptor, IL-18R1, and the beta-receptor, AcPL, both of which dimerize following ligand binding to the alpha component, initiating signal transduction by AcPL (10). Murine studies have shown that IL-18 (11) inhibits HBV replication through induction of IFN-␥ (12, 13), which directly inhibits the HBV life cycle at the pre-and posttranslational level. In vitro studies have recently shown that, similar to IL-1 (4), overexpression of IL-18 inhibits HBV replication in a hepatoma cell line (14), although the mechanism for this inhibition is unclear, as hepatocytes do not produce IFN-␥.NK cells are lymphocytes that eliminate virus-infected cells by both direct cytolysis and the production of several antiviral cytokines, including IFN-␥. HBV infection stimulates NK cells, most likely via the activation of DCs and macrophages that produce and chemokines, including CXCR3 (15). NK cells

Characterization of the Inflammasome in Human Kupffer Cells in Response to Synthetic Agonists and Pathogens

“…The nonstructural HBx protein encoded by HBV has been shown to affect RIG-I-MDA5 signaling in vitro (42). Furthermore, a previous study showed diminished IL-18 responses and reduced IFN-g of NK cells in differentiated monocytes from PBMC (43). HBV polymerase and HBs have been shown to affect the signaling of transcription factors associated with IFN transcription, such as IRF3 and IRF7 (15,44,45).…”

Differential expression of innate immune response genes in clinical phases of chronic hepatitis B infection

“…Studies showed that the HBeAg downregulated IFN‐γ expression by NK cells compared to core proteins or HBsAg. In addition, serum from subjects with HBeAg‐positive CHB significantly downregulated IFN‐γ expression in NK cells derived from uninfected control individuals compared to serum from HBeAg‐negative patients or uninfected controls . Using HBV precore/core gene mutations in spontaneous HBeAg seroconversion, Wu et al.…”

A Review of Functional Motifs Utilized by Viruses

“…These interactions downregulate the interferon (IFN) pathway, regulate the expression of interferon-stimulated genes (ISGs), and suppress both cytokine-mediated immunity and anti-viral defense [22]. Similar mechanisms were suggested for equine herpesvirus-1 [31], hepatitis E virus [32], and hepatitis B virus [33].ISG15, a ubiquitin-like interferon-stimulated protein, is stimulated by interferon or viral infection [34,35]. ISG15 is cytokine-like protein that promotes antiviral immune response.…”