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.
Highlights
Sepsis is characterized by an excessive inflammatory response to infection and is a major cause of mortality[1]
In this work we demonstrate that these receptors control hepatic cytokine production and signalling during sepsis in vivo and that the thyroid hormone directly antagonizes interleukin 6 (IL-6) signalling in cultured hepatocarcinoma cells and macrophages, leading to reduced Signal Transducer and Activator of Transcription 3 (STAT3) transcriptional activity
We report a novel role for thyroid hormone receptors (TRs) and their ligands, the thyroid hormones, in the activation of signalling pathways that play an essential role in liver homeostasis and inflammation
Summary
Sepsis is characterized by an excessive inflammatory response to infection and is a major cause of mortality[1]. Activation of Signal Transducer and Activator of Transcription 3 (STAT3) and Nuclear Factor kappa-Light-chain-enhancer of Activated B Cells (NF-κB) by these cytokines plays a key role in the liver response to inflammation[3], controlling the expression of a large number of genes[5]. The actions of the thyroid hormones (L-thyroxine, T4, and 3,3′,5-triiodo-L-thyronine, T3) are mediated by binding to nuclear receptors (TRαand TRβ) These receptors act as ligand-dependent transcription factors by binding, generally as heterodimers with the retinoid X receptor (RXR), to thyroid hormone response elements in target genes or by modulating the activity of other transcription factors or signalling pathways[12]. In this work we demonstrate that these receptors control hepatic cytokine production and signalling during sepsis in vivo and that the thyroid hormone directly antagonizes IL-6 signalling in cultured hepatocarcinoma cells and macrophages, leading to reduced STAT3 transcriptional activity
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