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The Thyroid Hormone Receptors Inhibit Hepatic Interleukin-6 Signaling During Endotoxemia. | LitMetric

The Thyroid Hormone Receptors Inhibit Hepatic Interleukin-6 Signaling During Endotoxemia.

Sci Rep

Departamento de Fisiopatología Endocrina y del Sistema Nervioso, Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Madrid, Spain.

Published: August 2016

AI Article Synopsis

  • * In experiments with TR knockout mice, there was a down-regulation of inflammatory mediators, but increased STAT3 and ERK activity, suggesting that TRs might normally suppress these pathways.
  • * Thyroid hormone T3 was found to inhibit IL-6 signaling in certain cells, reducing gene transcription and suggesting that TRs play a crucial role in managing inflammation and immune responses during sepsis by providing negative feedback to prevent excessive signaling.

Article Abstract

Decreased thyroidal hormone production is found during lipopolysaccharide (LPS)-induced endotoxic shock in animals as well as in critically ill patients. Here we studied the role of the thyroid hormone receptors (TRs) in activation of STAT3, NF-κB and ERK, which play a key role in the response to inflammatory cytokines during sepsis. TR knockout mice showed down-regulation of hepatic inflammatory mediators, including interleukin 6 (IL-6) in response to LPS. Paradoxically, STAT3 and ERK activity were higher, suggesting that TRs could act as endogenous repressors of these pathways. Furthermore, hyperthyroidism increased cytokine production and mortality in response to LPS, despite decreasing hepatic STAT3 and ERK activity. This suggested that TRs could directly repress the response of the cells to inflammatory mediators. Indeed, we found that the thyroid hormone T3 suppresses IL-6 signalling in macrophages and hepatocarcinoma cells, inhibiting STAT3 activation. Consequently, the hormone strongly antagonizes IL-6-stimulated gene transcription, reducing STAT3 recruitment and histone acetylation at IL-6 target promoters. In conclusion, TRs are potent regulators of inflammatory responses and immune homeostasis during sepsis. Reduced responses to IL-6 should serve as a negative feedback mechanism for preventing deleterious effects of excessive hormone signaling during infections.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971531PMC
http://dx.doi.org/10.1038/srep30990DOI Listing

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