Abstract
It is widely accepted that chronic hepatitis B virus (HBV) infection is the result of an ineffective antiviral immune response against HBV infection. Our previous study found that the hepatitis B surface Ag (HBsAg) was related to decreased cytokine production induced by the TLR2 ligand (Pam3csk4) in PBMCs from chronic hepatitis B patients. In this study, we further explored the mechanism involved in the inhibitory effect of HBsAg on the TLR2 signaling pathway. The results showed that both Pam3csk4-triggered IL-12p40 mRNA expression and IL-12 production in PMA-differentiated THP-1 macrophage were inhibited by HBsAg in a dose-dependent manner, but the production of IL-1β, IL-6, IL-8, IL-10, and TNF-α was not influenced. The Pam3csk4-induced activation of NF-κB and MAPK signaling were further examined. The phosphorylation of JNK-1/2 and c-Jun was impaired in the presence of HBsAg, whereas the degradation of IκB-α, the nuclear translocation of p65, and the phosphorylation of p38 and ERK-1/2 were not affected. Moreover, the inhibition of JNK phosphorylation and IL-12 production in response to Pam3csk was observed in HBsAg-treated monocytes/macrophages (M/MΦs) from the healthy donors and the PBMCs and CD14-positive M/MΦs from chronic hepatitis B patients. Taken together, these results demonstrate that HBsAg selectively inhibits Pam3csk4- stimulated IL-12 production in M/MΦs by blocking the JNK-MAPK pathway and provide a mechanism by which HBV evades immunity and maintains its persistence.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anthracenes / pharmacology
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Cell Differentiation
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Cell Line, Tumor
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Enzyme Activation
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Hepatitis B Surface Antigens / immunology
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Hepatitis B Surface Antigens / metabolism*
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Hepatitis B virus / immunology
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Hepatitis B, Chronic / immunology
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Hepatitis B, Chronic / virology
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Humans
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I-kappa B Proteins
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Immune Evasion / immunology*
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Interleukin-10 / biosynthesis
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Interleukin-12 / biosynthesis
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Interleukin-12 / metabolism*
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Interleukin-12 Subunit p40 / biosynthesis
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Interleukin-12 Subunit p40 / genetics
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Interleukin-1beta / biosynthesis
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Interleukin-6 / biosynthesis
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Interleukin-8 / biosynthesis
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JNK Mitogen-Activated Protein Kinases / immunology
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JNK Mitogen-Activated Protein Kinases / metabolism*
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Lipopeptides / metabolism
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Macrophages / metabolism
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Monocytes / metabolism
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NF-KappaB Inhibitor alpha
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NF-kappa B / metabolism
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Phosphorylation
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Toll-Like Receptor 2 / immunology
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Toll-Like Receptor 2 / metabolism*
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Transcription Factor RelA / metabolism
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Tumor Necrosis Factor-alpha / biosynthesis
Substances
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Anthracenes
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Hepatitis B Surface Antigens
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I-kappa B Proteins
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Interleukin-12 Subunit p40
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Interleukin-1beta
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Interleukin-6
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Interleukin-8
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Lipopeptides
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NF-kappa B
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NFKBIA protein, human
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Pam(3)CSK(4) peptide
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RNA, Messenger
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TLR2 protein, human
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Toll-Like Receptor 2
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Transcription Factor RelA
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Tumor Necrosis Factor-alpha
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Interleukin-10
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NF-KappaB Inhibitor alpha
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Interleukin-12
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pyrazolanthrone
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Extracellular Signal-Regulated MAP Kinases
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JNK Mitogen-Activated Protein Kinases