Hepatitis B Virus Surface Antigen Selectively Inhibits TLR2 Ligand-Induced IL-12 Production in Monocytes/Macrophages by Interfering with JNK Activation

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-1 beta, IL-6, IL-8, IL-10, and TNF-alpha was not influenced. The Pam3csk4-induced activation of NF-kappa B 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 I kappa B-alpha, 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/M(Phi)s) from the healthy donors and the PBMCs and CD14-positive M/M(Phi)s from chronic hepatitis B patients. Taken together, these results demonstrate that HBsAg selectively inhibits Pam3csk4-stimulated IL-12 production in M/M(Phi)s by blocking the JNK-MAPK pathway and provide a mechanism by which HBV evades immunity and maintains its persistence.