Interleukin 6 inhibits HBV entry through NTCP down regulation

Abstract

Hepatitis B virus (HBV) infection is a major public health problem. Recently, the human liver bile acid transporter Na(+)/taurocholate cotransporting polypeptide (NTCP) has been identified as an HBV specific receptor. NTCP expression is known to be strongly regulated by IL-6. This study was aimed at characterizing the effect of IL-6 on HBV entry. HBV entry was inhibited by up to 90% when cells were pretreated with IL-6 as shown by a strong inhibition of long term HBsAg secretion. This effect was confirmed by showing a severe reduction of intracellular HBV cccDNA. In parallel, we observed a 98% decrease in NTCP mRNA steady state level and an 80% reduction in NTCP-mediated taurocholate uptake. IL-6-mediated inhibition of NTCP-mediated taurocholate uptake and viral entry exhibited similar dose-dependence and kinetics while restoration of NTCP expression suppressed the inhibitory effect of IL-6. NTCP-mediated HBV entry is therefore markedly inhibited by IL-6.

Regulation of Plasma Membrane Localization of the Na+-Taurocholate Cotransporting Polypeptide (Ntcp) by Hyperosmolarity and Tauroursodeoxycholate

“…The findings are not only of interest for the understanding of hepatocellular bile acid handling and TUDC action in liver, but may also be relevant for hepatitis B virus entry into the hepatocyte, which was recently shown to be mediated by NTCP (51). Indeed, recent data suggest that interleukin-6 inhibits hepatitis B virus entry into the hepatocyte through down-regulation of NTCP (52).…”

Involvement of Interleukin 6 in Hepatitis B Viral Infection

“…However, other studies have arrived at contradictory conclusions. One study reported that IL-6 strongly inhibited HBV entry [40], which is inconsistent with previous studies [39]. Sodium taurocholate cotransporting polypeptide (NTCP) is a multiple transmembrane transporter predominantly expressed in the liver [50], and is recognized as an HBV-specific receptor that binds to the N-terminal part of the pre-S1 region of the large envelope protein [51].…”

“…Conversely, IL-6 can also mediate HBV entry into hepatocytes [39]. However, there are also conflicting reports that IL-6 inhibits HBV entry through the down-regulation of an HBV-specific receptor [40]. IL-6 also induces an inhibitory effect on HBV replication [41].…”

Unusual Features of Sodium Taurocholate Cotransporting Polypeptide as a Hepatitis B Virus Receptor

“…Conversely, introduction of NTCP cDNA into HepG2 and Huh7 cells conferred susceptibility to infection by HBV and HDV, respectively (16). These seminal findings established NTCP as an HBV and HDV receptor, a demonstration that has been independently confirmed and extended (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Consequently, NTCP substrates or inhibitors such as tauroursodeoxycholic acid (TUDCA), cyclosporine, irbesartan, and ritonavir could suppress ccHBV or HDV infection (18,(20)(21)(22)(23)(24).…”