Dual effects of interleukin-18: inhibiting hepatitis B virus replication in HepG2.2.15 cells and promoting hepatoma cells metastasis

Am J Physiol Gastrointest Liver Physiol. 2011 Sep;301(3):G565-73. doi: 10.1152/ajpgi.00058.2011. Epub 2011 Jun 30.

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-κB. 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-κB-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-κB played a critical role in both effects. Our work contributed to a deeper understanding of the biological function of IL-18 in human hepatocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / physiopathology
  • Cell Line
  • Cell Movement / drug effects
  • Hep G2 Cells
  • Hepatitis B virus / drug effects*
  • Hepatitis B virus / physiology
  • Humans
  • Interleukin-18 / physiology*
  • Liver Neoplasms / pathology
  • Liver Neoplasms / physiopathology
  • Matrix Metalloproteinase 3 / biosynthesis
  • Matrix Metalloproteinase 9 / biosynthesis
  • NF-kappa B / pharmacology
  • Neoplasm Metastasis / physiopathology
  • RNA, Messenger / metabolism
  • Receptors, Interleukin-18 / biosynthesis
  • Up-Regulation
  • Virus Replication / drug effects

Substances

  • Interleukin-18
  • NF-kappa B
  • RNA, Messenger
  • Receptors, Interleukin-18
  • Matrix Metalloproteinase 3
  • Matrix Metalloproteinase 9