Expression and DNA-binding activity of signal transducer and activator of transcription3 in alcoholic cirrhosis compared to normal liver and PBC in humans

In rats, activation of the cytokine-inducible transcription factor signal transducer and activator of transcription 3 (Stat3) is impaired in the liver after ethanol administration. The aim was to examine Stat3 expression, localization, and activity in alcoholic liver disease (ALD) in humans. Explanted livers of AID patients were compared to normal and primary biliary cirrhosis livers. Protein expression, DNA-binding, and subcellular localization of Stat3 was examined by Western blotting, electrophoretic mobility shift assays, and immunohistochemistry; and interleukin-6, Stat3, and suppressor of cytokine signaling (SOCS)-3 mRNA expression by quantitative polymerase chain reaction. Stat3 proteins increased markedly in AID, mainly in hepatocyte and proliferating biliary epithelial cell nuclei. in contrast to normal and primary biliary cirrhosis livers where Stat3 DNA-binding occurred normally, no Stat3 DNA-binding complexes were observed in AID, although the tyrosine and serine phosphorylation of Stat3 was not altered. Elevated interleukin-6 mRNA was found in AID whereas Stat3 and suppressor of cytokine signalling-3 mRNA levels were decreased. Although end-stage AID is characterized by up-regulation of Stat3 proteins, this transcription factor appears to be functionally inactive. Furthermore, decreased transcription of the Stat3 gene in AID might also affect cytoplasmic reserves of inactivated Stat3 in the long term. Impaired activation and restoration of Stat3 might thus contribute to the development of cell damage leading to liver cirrhosis in ALD.