Role of Toll-like receptor 2 in the immune response against hepadnaviral infection

Abstract

The Toll-like receptor 2 (TLR2) has recently been recognized to play an important role in the pathogenesis of chronic hepatitis B virus (HBV) infection. In the present study, we examined the role of TLR2 in hepadnaviral infection in hepatoma cell lines and the woodchuck model. The expression of TLR2 and pro-inflammatory cytokines was quantified by real time RT-PCR. TLR2-associated signaling pathways in hepatocytes were examined by Western blot. HBV replication and gene expression were assessed by Southern blot, Northern blot and specific ELISA, respectively. TLR2 ligands activated NF-κB, PI3K/Akt, and different arms of MAPK signaling pathways and induced the production of pro-inflammatory cytokines in hepatocytes. TLR2-mediated innate immune responses led to reduction of HBV/woodchuck hepatitis virus (WHV) replication and gene expression in HepG2.2.15 cells and primary woodchuck hepatocytes. Furthermore, the antiviral activity of TLR2 ligands was abolished by pretreatment with U0126 and rapamycin, inhibitors of the MAPK/ERK and PI3K/Akt pathways, respectively. In the woodchuck model, relatively low levels of TLR2 expression were found in peripheral blood mononuclear cells (PBMCs) and in liver tissues from chronic WHV carriers. TLR2 expression in PBMCs was inversely correlated with WHV DNA titers in acute WHV infection and in entecavir-treated chronic WHV carriers. These data suggest that hepatocytes play an active role in TLR2-mediated antiviral responses during hepadnaviral infection. The mutual inhibition of HBV replication and TLR2 signaling represents an important aspect of HBV infection and should be considered in the new therapeutic concept against chronic HBV infection.