Ethanol rapidly inhibits IL-6-activated STAT3 and C/EBP mRNA expression infreshly isolated rat hepatocytes'

The ability of ethanol to inhibit regenerative processes in the liver is th ought to play a keg role in the development of alcoholic liver disease. To understand the underlying mechanisms, me investigated the effects of ethano l on the Janus kinase-signal transducer and activator transcription factor (JAK-STAT) signaling pathways in hepatocytes, Treatment of freshly isolated adult rat hepatocytes with 10-100 mM ethanol rapidly (<3 min) inhibits int erleukin-6 (IL-6)-induced STAT3 activation, tyrosine and serine phosphoryla tion and IL-6-induced CCAAT enhancer binding protein (C/EBP) alpha and beta mRNA expression. Western analyses, in vitro kinase assays and in vivo cell labelling assays indicate that this inhibitory effect is not due to blocki ng the upstream-located JAK1, JAK2 or Tyk2 activation. On the contrary, acu te ethanol exposure significantly potentiates IL-6-induced JAK1 autophospho rylation in vitro and in vivo. Pretreatment with sodium vanadate, a non-sel ective tyrosine phosphatase inhibitor, or with MG132 and lactacystin, prote asome inhibitors, does not abolish the ethanol inhibition of IL-6-induced S TAT3 activation, suggesting that activation of protein tyrosine phosphatase s or the ubiquitin-proteasome pathway is not involved. In view of the criti cal role of IL-6 signaling in liver regeneration, these findings suggest th at the ability of biologically relevant concentrations of ethanol to marked ly inhibit IL-6-induced STAT3 phosphorylation is one of the cellular mechan isms involved in the pathogenesis and progression of alcoholic liver diseas es. (C) 1999 Federation of European Biochemical Societies.