Basic-liver, pancreas, and biliary tractHepatitis C core and nonstructural 3 proteins trigger toll-like receptor 2-mediated pathways and inflammatory activation
Section snippets
Reagents
Phenol-purified lipopolysaccharide (pLPS) was kindly provided by Dr. Latz E. (University of Massachusetts Medical School, Worcester, MA). S aureus peptidoglycan (PGN) was purchased from Fluka (Milwaukee, WI), zymosan from Sigma (St. Louise, MO), PAM2CSK4 and PAM3CSK4 from EMC Microcollections GmbH (Germany), fetal calf serum from HyClone (Logan, UT), and cell culture media D-MEM and RPMI1640 from Gibco (Grand Island, NY). Recombinant hepatitis C core, NS3, NS4, and NS5 proteins were purchased
HCV core and NS3 proteins trigger cellular activation via toll-like receptor 2
Increasing evidence suggests that, in addition to recognition of bacterial and fungal pathogens, toll-like receptors are also involved in recognition of viral pathogens. TLR-mediated “danger” signals contribute to activation of innate immune responses to trigger viral elimination and inflammatory responses. We, and others, have reported that there is increased proinflammatory activation in patients with chronic HCV infection, including increased monocyte TNF-α production.7, 8 We have recently
Discussion
Although the mechanisms of hepatitis C viral replication have been extensively studied, little is known about the molecular mechanisms by which immune cells recognize HCV. Here we demonstrate that the pattern recognition receptor TLR2 is required to recognize components of the HCV polyprotein. Our data show that HCV core and NS3 but not E2 proteins activate innate immune cells in a TLR2-dependent fashion and result in downstream induction of TLR2-specific intracellular signaling pathways that
References (57)
- et al.
Decreased frequency of HCV core-specific peripheral blood mononuclear cells with type 1 cytokine secretion in chronic hepatitis C
J Hepatol
(1999) - et al.
Interaction between hepatitis C virus proteins and host cell factors
Curr Opin Microbiol
(2002) - et al.
Replication of the hepatitis C virus
Baillieres Best Pract Res Clin Gastroenterol
(2000) - et al.
Features of the CD4+ T-cell response in liver and peripheral blood of hepatitis C virus-infected patients with persistently normal and abnormal alanine aminotransferase levels
J Hepatol
(2002) - et al.
Nonstructural 3 protein of hepatitis C virus triggers an oxidative burst in human monocytes via activation of NADPH oxidase
J Biol Chem
(2001) - et al.
DC-SIGN and L-SIGN are high affinity binding receptors for hepatitis C virus glycoprotein E2
J Biol Chem
(2003) - et al.
Recognition of microbial infection by Toll-like receptors
Curr Opin Immunol
(2003) - et al.
TLR signaling pathways
Semin Immunol
(2004) - et al.
Lipopolysaccharide rapidly traffics to and from the Golgi apparatus with the toll-like receptor 4-MD-2-CD14 complex in a process that is distinct from the initiation of signal transduction
J Biol Chem
(2002) - et al.
The extracellular Toll-like receptor 2 domain directly binds peptidoglycan derived from Staphylococcus aureus
J Biol Chem
(2002)
Role of TLR-2 in the activation of nuclear factor-κB by oxidative stress in cardiac myocytes
J Biol Chem
Toll-like receptor 2 contributes to liver injury by Salmonella infection through Fas ligand expression on NKT cells in mice
Gastroenterology
Peripheral blood mononuclear cell expression of Toll-like receptors and relation to cytokine levels in cirrhosis
Hepatology
Cytokines as predictors for sustained response and as markers for immunomodulation in patients with chronic hepatitis C
Clin Biochem
Identification of hTLR10a novel human Toll-like receptor preferentially expressed in immune cells
Biochim Biophys Acta
Hepatitis C virus NS5A and subgenomic replicon activate NF-κB via tyrosine phosphorylation of IκBα and its degradation by calpain protease
J Biol Chem
Serum levels of hepatitis C virus core protein in patients with chronic hepatitis C treated with interferon alfa
Hepatology
Hepatitis C virus core and nonstructural proteins induce fibrogenic effects in hepatic stellate cells
Gastroenterology
Pathogenesis, natural history, treatment, and prevention of hepatitis C
Ann Intern Med
Analysis of successful immune responses in persons infected with hepatitis C virus
J Exp Med
Determinants of viral clearance and persistence during acute hepatitis C virus infection
J Exp Med
Impaired effector function of hepatitis C virus-specific CD8+ T cells in chronic hepatitis C virus infection
J Immunol
Th1/Th2 cytokine profiles and their relationship to clinical features in patients with chronic hepatitis C virus infection
J Gastroenterol
Evidence for lack of cross-genotype protection of CD4+ T cell responses during chronic hepatitis C virus infection
Clin Exp Immunol
Hepatitis C virus core and nonstructural protein 3 proteins induce pro- and anti-inflammatory cytokines and inhibit dendritic cell differentiation
J Immunol
Pathogenesis of chronic hepatitis Cimmunological features of hepatic injury and viral persistence
Hepatology
Suppression of host immune response by the core protein of hepatitis C viruspossible implications for hepatitis C virus persistence
J Immunol
Hepatitis C virus core protein inhibits Fas- and tumor necrosis factor-α-mediated apoptosis via NF-κB activation
J Virol
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Toll-like receptor 2 signaling in liver pathophysiology
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2019, Cytokine and Growth Factor ReviewsCitation Excerpt :NS3 upregulated expression of IL-6 and TNF-α in the microglial cell line CHME3 via TLR2/TLR6 binding and downstream activation of the MyD88/NF-κB pathway [30]. NS3 or the core protein stimulated expression of TNF-α or IL-6 in PBMCs, monocytes, macrophages or HEK cells via TLR2, with TLR1 and TLR6 as co-receptors [27,28,48]. Additionally, NS3, NS4 and NS5 induced the expression of IL-1β or TNF-α in primary human Kupffer cells.
Supported by PHS grant AA12862 and by the resources of University of Massachusetts Medical School CFAR and DERC core facilities.