Tumor necrosis factor α (TNF-α)-induced RANTES chemokine expression via activation of NF-κB and p38 MAP kinase: roles of TNF-α in alcoholic liver diseases

Background/Aims: Increased concentration of plasma tumor necrosis factor α (TNF-α) correlates with the clinical course of alcoholic liver diseases. In addition, hepatic RANTES which migrates CD4 T lymphocytes to liver is increased in patients with alcoholic hepatitis. We investigated that roles of TNF-α on RANTES expression in hepatocytes. Methods: HLE cells were treated with TNF-α in the presence, or absence of several inhibitors. Enzyme-linked immunoassay and reverse transcriptase-polymerase chain reaction were performed for the measurement of protein production and mRNA of RANTES, respectively. Moreover, DNA-binding activity of NF-κB was investigated using electrophoretic mobility shift assay. To examine effects of TNF-α on RANTES gene expression, luciferase assay was performed. Results: TNF-α clearly up-regulated RANTES expression in a time-dependent fashion and induced DNA-binding activity of NF-κB. Moreover, TNF-α-induced RANTES expression was completely inhibited by SB203580, but not calphostin C and wortmannin. Luciferase assay showed that TNF-α increased RANTES gene expression and mutation of NF-κB binding sites in the RANTES promoter ablated TNF-α inducibility. Conclusions: We showed that RANTES was transcriptionally induced in human hepatoma cells by treatment with TNF-α via activation of NF-κB and p38 MAP kinase, presumably suggesting that TNF-α-induced expression of RANTES plays important roles in cell-mediated liver injury in alcoholic liver diseases.