title: Hepatitis B virus surface antigen selectively inhibits TLR2 ligand-induced IL-12 production in monocytes/macrophages by interfering with JNK activation.
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.
authors.affiliation: Key Laboratory of Medical Molecular Virology, Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai 200032, China.
authors.forename: Sen
authors.initials: S
authors.lastname: Wang
authors.forename: Zhiao
authors.initials: Z
authors.lastname: Chen
authors.forename: Conghua
authors.initials: C
authors.lastname: Hu
authors.forename: Fangxing
authors.initials: F
authors.lastname: Qian
authors.forename: Yuming
authors.initials: Y
authors.lastname: Cheng
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.forename: Bisheng
authors.initials: B
authors.lastname: Shi
authors.forename: Jieliang
authors.initials: J
authors.lastname: Chen
authors.forename: Yunwen
authors.initials: Y
authors.lastname: Hu
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Yuan
mesh_terms: D000873:Anthracenes / Q000494:pharmacology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006514:Hepatitis B Surface Antigens / Q000276:immunology / Q000378:metabolism*; D006515:Hepatitis B virus / Q000276:immunology; D019694:Hepatitis B, Chronic / Q000276:immunology / Q000821:virology; D006801:Humans; D020672:I-kappa B Proteins; D057131:Immune Evasion / Q000276:immunology*; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis / Q000378:metabolism*; D053762:Interleukin-12 Subunit p40 / Q000096:biosynthesis / Q000235:genetics; D053583:Interleukin-1beta / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism*; D055666:Lipopeptides / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000873:Anthracenes; D006514:Hepatitis B Surface Antigens; D020672:I-kappa B Proteins; D053762:Interleukin-12 Subunit p40; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D055666:Lipopeptides; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C508075:Pam(3)CSK(4) peptide; D012333:RNA, Messenger; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D000072000:NF-KappaB Inhibitor alpha; D018664:Interleukin-12; C432165:pyrazolanthrone; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases