The JAK-STAT (Janus Kinase - Signal Transducer and Activator of Transcription) signaling pathway activated by more than 35 different cytokines or growth factors has been implicated in a variety of cellular functions in the hematopoietic, immune, neuronal and hepatic systems. Ethanol inhibition of JAK-STAT activation may be a mechanism by which ethanol causes a wide variety of disorders in many organs. Acute exposure of rat hepatocytes to 25-100 mM ethanol significantly inhibits interleukin 6-, interferon gamma- or growth hormone-induced STAT activation. Chronic ethanol consumption significantly attenuates hepatic STAT3 activation induced by partial hepatectomy or interleukin 6. Acute ethanol (25-100 mM) exposure also significantly attenuates thrombopoietin- or interleukin 6-induced STAT activation in hematopoietic cells (BAF3/mp1 cells, platelets, U937, and AF10 cells), and ciliary neurotrophic factor-induced STAT activation in neuronal cells (NBTF neuroblastoma). The target sites of ethanol in the JAK-STAT signaling pathway will be explored by analyzing the effects of ethanol on cytokine-induced STAT phosphorylation, dimerization, translocation, JAK phosphorylation, receptor phosphorylation and ligand-receptor binding. The effects of chronic ethanol on the JAK-STAT pathway will be explored by examining JAK-STAT activation in vivo in rats fed with an ethanol containing diet. Identification of ethanol inhibition of the JAK-STAT signaling pathway in various tissues will enhance our understanding of the pathogenesis and progression of a wide variety of disorders caused by ethanol, such as antiregenerative effects, thrombocytopenia and fetal alcohol syndrome, and may also prove helpful in the design of novel drugs with therapeutic potential in alcohol-related disorders.
