Abstract
There is limited information about the role of hepatic stellate cells (HSCs) in the liver innate immunity against hepatitis B virus (HBV) infection. We thus examined whether hepatic stellate cell line (LX-2) can be immunologically activated and produce antiviral factors that inhibit HBV replication in HepG2 cells. We found that LX-2 cells expressed the functional Toll-like receptor 3 (TLR3), activation of which by PolyI:C resulted in the selective induction of interferon-β (IFN-β) and IFN-λs, the phosphorylation of IFN regulatory factor 3 (IRF3) and IRF7. When HepG2 cells were treated with supernatant (SN) from PolyI:C-activated LX-2 cells, HBV replication was significantly inhibited. IFN-β and IFN-λ appeared to contribute to LX-2 SN-mediated HBV inhibition, as the antibodies to IFN-β and IFN-λ receptors could largely block the LX-2 SN action. Mechanistically, LX-2 SN treatment of the HepG2 cells induced a number of antiviral IFN-stimulated genes (ISGs: ISG20, ISG54, ISG56, OAS-1, Trim22, and Trim25) and facilitated the phosphorylation of STATs. These observations support further studies on the role of HSCs in the liver innate immunity against HBV infection.
Highlights
Hepatitis B virus (HBV) infection is a frequent cause of severe liver diseases including liver cirrhosis and hepatocellular carcinoma [1]
We first examined whether PolyI:C could activate Toll-like receptor 3 (TLR3) in human hepatic stellate cells (LX-2)
PolyI:C was added into the LX-2 cell cultures and we found it had little effect on TLR3 activation in LX-2 cells (Supplementary Figure 1)
Summary
Hepatitis B virus (HBV) infection is a frequent cause of severe liver diseases including liver cirrhosis and hepatocellular carcinoma [1]. HBV DNA can integrate into host cell genome or present as non-integrated covalently closed circular DNA (cccDNA), which serves as a template for virus replication and persistent infection [2]. To establish and maintain persistent replication, HBV has evolved multiple strategies to evade the host innate and adaptive immune responses [4]. Lebosse et al reported that the innate immune responses were impaired in untreated patients with chronic HBV infection [5]. HBV can suppress TLR-mediated innate immune response in the liver cells [7]. A recent study reported that HBV infection had little effect on signal pathway of pattern recognition receptors, and failed to induce IFN and IFN-stimulated genes in human hepatocytes [8]. Suslov et al showed that liver tissues from HBV-infected patients did not induce the innate immune
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