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

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Abstract
The proinflammatory cytokine tumor necrosis factor (TNF) α is mainly produced in cells from the monocyte/macrophage lineage. TNFα is also a key signaling molecule in the liver functioning as an important physiological and pathogenic mediator. In hepatocytes or human hepatoma cells TNFα is expressed at extremely low levels but TNFα biosynthesis can be induced by interleukin (IL)‐1β or 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA). Here, we show that IL‐1β and TPA stimulated TNFα gene transcription in hepatoma cells mediated by a composite TPA‐responsive element/cAMP response element. Both IL‐1β 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 TNFα promoter activity and secretion of TNFα. Expression of the nuclear dual‐specific MAP kinase phosphatase‐1 (MKP‐1) blocked TNFα promoter activity and TNFα secretion following IL‐1β or TPA stimulation, indicating that MKP‐1 functions as a nuclear shut‐of‐device of IL‐1β and TPA‐induced TNFα expression. J. Cell. Biochem. 100: 242–255, 2007.