Cytokine-mediated differential induction of hepatic activator protein-1 genes

Background. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) increase the synthesis of hepatic acute-phase proteins; these effects appear mediated by activation of transcription factors. The purpose of this study was to determine the effects of TNF-α and IL-6 on expression of the jun family of activator protein-1 (AP-1) transcription factors with the human hepatoma cell line HepG2, a well-characterized model of the hepatic acute- phase response. Methods. HepG2 cells, treated with either TNF-α (100 ng/ml) or IL-6 (10 ng/ml), were extracted for RNA and protein (total and nuclear) and analyzed. Results. TNF-α increased c-jun and junD mRNA and c-Jun and JunD protein levels, as well as AP-1 binding activity. IL-6 increased c-jun mRNA, c-Jun protein, and AP-1 binding activity but did not affect either junD or junB expression. Conclusions. TNF-α and IL-6 induce a differential pattern of AP-1 expression in HepG2 cells; TNF-α increases both c-Jun and JunD, whereas IL-6 stimulates only c-Jun. Neither TNF-α nor IL-6 stimulates JunB. Multiple cytokines, released during stress, may act in concert to stimulate the AP-1 proteins, which ultimately culminate in the downstream synthesis of a variety of acute-phase proteins.