Effects of short and long term ethanol on the activation of signal transducer and activator transcription factor 3 in normal and regenerating liver.

Interleukin-6 (IL-6) induced activation of Signal Transducer and Activator Transcription Factor 3 (Stat3) is a critical step in liver regeneration. Chronic ethanol consumption is known to increase the plasma concentration of IL-6, yet the ability of the liver to regenerate and the regenerative induction of several IL-6 initiated events are impaired in chronic alcoholic liver disease. We hypothesized that chronic ethanol consumption inhibits IL-6 dependent signal transduction. To test this hypothesis, the effect of ethanol on the Stat3 signal transduction pathway was studied in the adult rat liver. In vitro treatment of freshly isolated normal adult rat hepatocytes with 50-100 mM ethanol for 30 min blocked IL-6-induced Stat3 activation. Long-term ethanol intake in vivo significantly attenuated the activation of Stat3 induced either in vivo by partial hepatectomy or in vitro by IL-6. In contrast, short-term ethanol consumption enhanced the regenerative induction of Stat3 but inhibited IL-6 induced Stat3 activation. These data suggest that the inhibition of liver regeneration by chronic ethanol consumption is, at least in part, mediated by modulating the activation of Stat3.