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Endocrine Abstracts (2016) 41 EP771 | DOI: 10.1530/endoabs.41.EP771

Instituto de Investigaciones Biomédicas, Madrid, Spain.


The known functions of the thyroid hormones in the liver have expanded from their well-known roles in regulating metabolism to also participate in liver regeneration, senescence and hepatocarcinogenesis. The transcription factors STAT3 and NF-κB play a key role in liver homeostasis, in the response to infection and inflammation and in hepatocarcinoma development. Interleukin 6 (IL-6) and Tumour Necrosis α (TNFα) are the best-known cytokines responsible for hepatic stimulation of these signalling pathways. We have analysed the effect of thyroid hormones in the response of hepatocarcinoma cells to these factors. We found that triiodothyronine (T3) suppresses IL-6 signalling in cultured Hep3B cells, inhibiting the activation of the main cytokine downstream targets: STAT3 and ERK. In contrast, no inhibitory effects of T3 in the NF-κB response to TNFα were observed. In agreement with these results, T3 strongly antagonized IL-6 stimulated activity of a reporter plasmid bearing STAT-binding elements, while the hormone did not reduce activation by TNFα of a reporter plasmid containing NF-κB binding sites. Transcript levels of the IL-6 receptor or Gp130, essential for IL-6 signal transduction were not altered by T3, but the hormone significantly reduced stimulation by IL-6 of STAT target genes encoding acute-phase proteins, which are key components of the hepatic response to the cytokine. In chromatin immunoprecipitation assays, T3 significantly reduced STAT3 recruitment to its target promoters in response to IL-6. Moreover, IL-6 dependent increase of acetylated histone H4, a marker of transcriptional activation, was also suppressed by T3. Our results show that the thyroid hormones can counteract the cellular responses to IL-6 reducing its transcriptional actions. Through this mechanism, the thyroid hormones may modulate immune homeostasis and carcinogenesis in the liver, suggesting that they could be important targets for developing new therapeutic strategies for the treatment of liver diseases.

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