Background/Aims: The hepatitis B virus X protein (HBx), a major viral transactivator, is implicated in hepatic inflammation, since it induces many pro-inflammatory cytokines at transcriptional level. The aim of this study was to investigate role of HBx in expression of interleukin 18 (IL-18), a newly identified cytokine that up-regulates Fas ligand (FasL) expression. Methods: Chang X-34 that expressing HBx under the control of a doxycycline-inducible promoter, and hepatitis B virus (HBV)-integrated hepatoma cell lines were examined for IL-18 expression by Northern and Western blotting analysis. To test the role of IL-18 produced by hepatoma cells, FasL expression was examined by flow cytometry after treatment with neutralizing anti-IL-18 antibodies. Further, IL-18 expression was examined in the liver tissues of HBx-transgenic mice. Results: Induction of IL-18 following HBx expression in Chang X-34 and the pattern of IL-18 expression in HBV-integrated cell lines, implicated that HBx transcriptionally induces IL-18 expression. Neutralizing anti-IL-18 antibodies blocked the expression of FasL, suggesting that IL-18 plays a critical role in FasL expression. Further, IL-18 expression in the HBx-transgenic liver, was correlated with the degree of hepatitis. Conclusions: Our results demonstrated that HBx induces IL-18 expression in liver, which may be associated with hepatic injury by amplifying FasL expression during HBV infection.
Bibliographical noteFunding Information:
We thank Dr H. Tsutsi (Hyogo College of Medicine, Hyogo, Japan) for providing the IL-18-responsive LNK5E3 cells. This study was supported by a grant of the 2000 Good Health R&D Project (HMP-00-B-21200-0043 to M.O.L) from the Ministry of Health and Welfare, Korea.
- Fas ligand
- Hepatitis B virus X protein
- Interleukin 18
- Liver injury