Hepatitis B virus X protein induced expression of interleukin 18 (IL-18): a potential mechanism for liver injury caused by hepatitis B virus (HBV) infection.
OBJECTIVE
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.
Lee
Mi-Ock
MO
Department of Bioscience and Biotechnology, Sejong University, 98 Kunja-dong, Kwangjin-gu, Seoul 140-747, South Korea. molee@sejong.ac.kr
Choi
Youn-Hee
YH
Shin
Eui-Cheol
EC
Kang
Hyo-Jin
HJ
Kim
Young-Mee
YM
Jeong
Su-Yon
SY
Seong
Je Kyung
JK
Yu
Dae-Yeul
DY
Cho
Hyeseong
H
Park
Jeon Han
JH
Kim
Se Jong
SJ
D000818:Animals; D006528:Carcinoma, Hepatocellular; D053222:Fas Ligand Protein; D015967:Gene Expression Regulation, Viral; D006515:Hepatitis B virus / Q000502:physiology*; D019694:Hepatitis B, Chronic / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D022781:Hepatocytes / Q000276:immunology / Q000473:pathology / Q000821:virology; D006801:Humans; D020382:Interleukin-18 / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000473:pathology / Q000821:virology; D008113:Liver Neoplasms; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D015534:Trans-Activators / Q000235:genetics*; D014158:Transcription, Genetic / Q000502:physiology; D014407:Tumor Cells, Cultured; D054334:Viral Regulatory and Accessory Proteins
C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D020382:Interleukin-18; D008562:Membrane Glycoproteins; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein