title: Dual effects of interleukin-18: inhibiting hepatitis B virus replication in HepG2.2.15 cells and promoting hepatoma cells metastasis.
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.
authors: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei, China.
authors: Yijuan
authors: Y
authors: Zhang
authors: Yunbo
authors: Y
authors: Li
authors: Yifan
authors: Y
authors: Ma
authors: Shuhui
authors: S
authors: Liu
authors: Yinglong
authors: Y
authors: She
authors: Peng
authors: P
authors: Zhao
authors: Mingzhen
authors: M
authors: Jing
authors: Tao
authors: T
authors: Han
authors: Chao
authors: C
authors: Yan
authors: Zhenghui
authors: Z
authors: Wu
authors: Jinrong
authors: J
authors: Gao
authors: Linbai
authors: L
authors: Ye
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000503:physiopathology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D020382:Interleukin-18 / Q000502:physiology*; D008113:Liver Neoplasms / Q000473:pathology / Q000503:physiopathology; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D016328:NF-kappa B / Q000494:pharmacology; D009362:Neoplasm Metastasis / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D053724:Receptors, Interleukin-18 / Q000096:biosynthesis; D015854:Up-Regulation; D014779:Virus Replication / Q000187:drug effects
chemical_list: D020382:Interleukin-18; D016328:NF-kappa B; D012333:RNA, Messenger; D053724:Receptors, Interleukin-18; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9