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Keywords:

  • Alcohol;
  • Cytokines;
  • Transcription Factors;
  • TNF;
  • Jnk;
  • NF-kappa B

Cytokines, such as TNFα, modulate the behavior of many cells by regulating the expression of a wide array of genes. When a cytokine binds to its receptor on the cell surface, the receptor becomes activated and activates signal transduction cascades. These cascades typically involve a series of phosphorylation reactions that lead to sequential activation of various kinases. The targets of these kinases include DNA binding proteins that regulate the transcription of target genes. The activity of DNA binding proteins, such as c-Jun and NF-kappa B, titrates the transcriptional activity of cytokine-regulated genes. Both acute and chronic alcohol consumption of ethanol increase hepatic expression of TNFα. After acute ethanol consumption, this is associated with increased induction of several TNF-dependent regenerative events, including the activation of c-Jun and increased binding activity of NF-kappa B. However, chronic consumption of ethanol appears to impede TNFα signaling in the liver because it attenuates the increases in c-JUN activity and NF-kappa B binding, which normally follow partial hepatectomy. These results suggest that one mechanism by which ethanol influences liver cell behavior is by influencing local expression of TNFα and changing the activity of TNF-regulated transcription factors.