Dual effects of interleukin-18: Inhibiting hepatitis B virus replication in Hepg2.2.15 cells and promoting hepatoma cells metastasis

Yijuan Zhang, Yunbo Li, Yifan Ma, Shuhui Liu, Yinglong She, Peng Zhao, Mingzhen Jing, Tao Han, Chao Yan, Zhenghui Wu, Jinrong Gao, Linbai Ye

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

Interleukin-18 (IL-18) has been reported to inhibit hepatitis B virus (HBV) replication in the liver of HBV transgenic mice; however, the molecular mechanism of its antiviral effect has not been fully understood. In the present study, it was shown that IL-18 and its receptors (IL-18R) were constitutively expressed in hepatoma cell lines HepG2 and HepG2.2.15 as well as normal liver cell line HL-7702. We demonstrated that IL-18 directly inhibited HBV replication in HepG2.2.15 cells via downregulating the activities of HBV core and X gene promoters. The suppressed HBV replication by IL-18 could be rescued by the administration of BAY11-7082, an inhibitor of transcription factor NF-kB. On the other hand, it was of interest that IL-18 promoted HepG2 cell metastasis and migration dose dependently in both wound-healing assays and Transwell assays. The underlying mechanism could be partially attributable to the increased activities of extracellular matrix metalloproteinase (MMP)-9, MMP-3, and MMP-2 by IL-18, which upregulated the mRNA levels of MMP-3 and MMP-9 in a NF-kB-dependent manner. Furthermore, it was confirmed that expression of IL-18/IL-18R and most MMPs were remarkably upregulated in hepatocellular carcinoma (HCC) liver cancer tissue specimens, suggesting that IL-18/IL-18R-triggered signaling pathway was closely related to HCC metastasis in vivo. Therefore, we revealed the dual effects of IL-18 in human hepatocytes: it not only inhibited HBV replication but also promoted hepatoma cells metastasis and migration. NF-kB played a critical role in both effects. Our work contributed to a deeper understanding of the biological function of IL-18 in human hepatocytes.

Original languageEnglish
Pages (from-to)G565-G573
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume301
Issue number3
DOIs
StatePublished - Sep 2011
Externally publishedYes

Keywords

  • Extracellular matrix metalloproteinases
  • Hepatitis B virus
  • Hepatoma cells
  • Interleukin-18
  • Metastasis and migration

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