Interleukin-1beta and tetradecanoylphorbol acetate-induced biosynthesis of tumor necrosis factor alpha 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. TNFalpha is also a key signaling molecule in the liver functioning as an important physiological and pathogenic mediator. In hepatocytes or human hepatoma cells TNFalpha is expressed at extremely low levels but TNFalpha biosynthesis can be induced by interleukin (IL)-1beta or 12-O-tetradecanoylphorbol-13-acetate (TPA). Here, we show that IL-1beta and TPA stimulated TNFalpha gene transcription in hepatoma cells mediated by a composite TPA-responsive element/cAMP response element. Both IL-1beta 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 TNFalpha promoter activity and secretion of TNFalpha. Expression of the nuclear dual-specific MAP kinase phosphatase-1 (MKP-1) blocked TNFalpha promoter activity and TNFalpha secretion following IL-1beta or TPA stimulation, indicating that MKP-1 functions as a nuclear shut-of-device of IL-1beta and TPA-induced TNFalpha expression.