Ethanol rapidly inhibits IL‐6‐activated STAT3 and C/EBP mRNA expression in freshly isolated rat hepatocytes

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Abstract
The ability of ethanol to inhibit regenerative processes in the liver is thought to play a key role in the development of alcoholic liver disease. To understand the underlying mechanisms, we investigated the effects of ethanol 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 interleukin‐6 (IL‐6)‐induced STAT3 activation, tyrosine and serine phosphorylation and IL‐6‐induced CCAAT enhancer binding protein (C/EBP) α and β mRNA expression. Western analyses, in vitro kinase assays and in vivo cell labelling assays indicate that this inhibitory effect is not due to blocking the upstream‐located JAK1, JAK2 or Tyk2 activation. On the contrary, acute ethanol exposure significantly potentiates IL‐6‐induced JAK1 autophosphorylation in vitro and in vivo. Pretreatment with sodium vanadate, a non‐selective tyrosine phosphatase inhibitor, or with MG132 and lactacystin, proteasome inhibitors, does not abolish the ethanol inhibition of IL‐6‐induced STAT3 activation, suggesting that activation of protein tyrosine phosphatases or the ubiquitin‐proteasome pathway is not involved. In view of the critical role of IL‐6 signaling in liver regeneration, these findings suggest that the ability of biologically relevant concentrations of ethanol to markedly inhibit IL‐6‐induced STAT3 phosphorylation is one of the cellular mechanisms involved in the pathogenesis and progression of alcoholic liver diseases.