Interleukin-1β and tetradecanoylphorbol acetate-induced biosynthesis of tumor necrosis factor α in human hepatoma cells involves the transcription factors ATF2 and c-jun and stress-activated protein kinases

The proinflammatory cytokine tumor necrosis factor (TNF) alpha is mainly produced in cells from the monocyte/macrophage lineage. TNF alpha is also a key signaling molecule in the liver functioning as an important physiological and pathogenic mediator. in hepatocytes or human hepatoma cells TNF alpha is expressed at extremely low levels but TNF alpha biosynthesis can be induced by interleukin (IL)-1 beta or 12-O-tetradecanoylphorbol-13-acetate (TPA). Here, we show that IL-1 beta and TPA stimulated TNF alpha gene transcription in hepatoma cells mediated by a composite TPA-responsive element/cAMP response element. Both IL-1 beta and TPA triggered phosphorylation and activation of the basic region leucine zipper transcription factors c-Jun and ATF2 and expression of dominant-negative mutants of c-Jun and ATF2-reduced TNFa promoter activity and secretion of TNFa. Expression of the nuclear dual-specific MAP kinase phosphatase-1 (MKP-1) blocked TNF alpha promoter activity and TNF alpha secretion following IL-1 beta or TPA stimulation, indicating that MKP-1 functions as a nuclear shut-of-device of IL-1 beta and TPA-induced TNF alpha expression.