ALCOHOL AND CYTOKINE-INDUCIBLE TRANSCRIPTION FACTORS

Cytokines, such as TNF alpha, modulate the behavior of many cells by r egulating the expression of a wide array of genes. When a cytokine bin ds 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 DN A binding proteins that regulate the transcription of target genes. Th e activity of DNA binding proteins, such as c-Jun and NF-kappa B, titr ates the transcriptional activity of cytokine-regulated genes. Both ac ute and chronic alcohol consumption of ethanol increase hepatic expres sion of TNF alpha. 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 TNF alpha signaling in the liver because it attenuates the increases i n c-JUN activity and NF-kappa B binding, which normally follow partial hepatectomy. These results suggest that one mechanism by which ethano l influences liver cell behavior is by influencing local expression of TNF alpha and changing the activity of TNF-regulated transcription fa ctors.