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 anti-viral 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 IL-18 directly inhibited HBV replication in HepG2.2.15 cells via down-regulating 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 nuclear factor-kappaB (NF-κB). On the other hand, it was of interest that IL-18 promoted HepG2 cells 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 up-regulated 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 up-regulated in hepatocellular carcinoma (HCC)liver cancer tissue specimens, suggesting 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.
- hepatitis B virus
- hepatoma cells
- metastasis and migration
- extracellular matrix metalloproteinases
- Copyright © 2011, American Journal of Physiology- Gastrointestinal and Liver Physiology