Triiodothyronine Down-Regulates Thyrotropin-Releasing Hormone (TRH) Synthesis and Decreases pTRH-(160–169) and Insulin Releases from Fetal Rat Islets in Culture1

The endocrine system participates in regulating macrophage maturation, although little is known about the modulating role of the thyroid hormones. In vitro results demonstrate a negative role of one such hormone, triiodothyronine (T3), in triggering the differentiation of bone marrow-derived monocytes into unpolarized macrophages. T3-induced macrophages displayed a classically activated (M1) signature. A T3-induced M1-priming effect was also observed on polarized macrophages because T3 reverses alternatively activated (M2) activation, whereas it enhances that of M1 cells. In vivo, circulating T3 increased the content of the resident macrophages in the peritoneal cavity, whereas it reduced the content of the recruited monocyte-derived cells. Of interest, T3 significantly protected mice against endotoxemia induced by lipopolysaccharide i.p. injection; in these damaged animals, decreased T3 levels increased the recruited (potentially damaging) cells, whereas restoring T3 levels decreased recruited and increased resident (potentially beneficial) cells. These data suggest that the anti-inflammatory effect of T3 is coupled to the modulation of peritoneal macrophage content, in a context not fully explained by the M1/M2 framework. Thyroid hormone receptor expression analysis and the use of different thyroid hormone receptor antagonists suggest thyroid hormone receptor β1 as the major player mediating T3 effects on macrophages. The novel homeostatic link between thyroid hormones and the pathophysiological role of macrophages opens new perspectives on the interactions between the endocrine and immune systems.

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The Thyroid Hormone Triiodothyronine Controls Macrophage Maturation and Functions

Perrotta

Buldorini

Assi

et al. 2014

The American Journal of Pathology

106

101

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Molecular Evolution of the Thyrotrophin‐Releasing Hormone Precursor in Vertebrates: Insights From Comparative Genomics

Wallis

2010

J Neuroendocrinology

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Human preprothyrotrophin-releasing hormone (ppTRH) includes six copies of the TRH sequence, the rat and mouse precursors have five, and those of non-mammalian vertebrates have up to eight. In the present study, the evolutionary basis of this variation was investigated using ppTRH gene sequences extracted from available vertebrate genomic databases. A structure based on eight TRH repeats appears to be the norm for non-mammalian vertebrates, but in all mammals except monotremes this number is reduced to a maximum of six. In some species, one (or more) of the TRH repeats has been mutated, probably rendering it functionless and, in a few species, one or two copies of the TRH sequence have been deleted completely. Sequences of regions between the TRH sequences are poorly conserved, despite reports that several active peptides are produced from these regions. The 5' untranslated region of ppTRH is also very variable but, in eutherians, the promoter region immediately upstream of the gene is quite strongly conserved. In particular, those sequences identified as being involved in transcriptional regulation are well conserved in most eutherians, although they are largely absent from other vertebrates. In most species, gene order around the ppTRH locus is conserved, although exceptions include man and chimpanzee, as well as rat and mouse. The comparative genomics approach thus provides a wider view than previously available of the range of ppTRH genes in vertebrates, and of the species specificity displayed by this molecule.

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Role of Peroxisome Proliferator-Activated Receptor-γ Coactivator-1α in the Transcriptional Regulation of the Human Uncoupling Protein 2 Gene in INS-1E Cells

Oberkofler¹,

Klein²,

Felder³

et al. 2006

Endocrinology

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A role of uncoupling protein 2 (UCP2) as negative modulator of insulin secretion has been suggested, but the transcriptional pathways regulating beta-cell UCP2 gene expression have been established in rodents only. We show here that the underlying sequence motifs are not conserved in the human gene and provide evidence for regulatory mechanisms involving the transcriptional cofactor peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1alpha). PGC-1alpha potentiates thyroid hormone (T(3))-mediated transcriptional activation of the human UCP2 gene in INS-1E cells. Two thyroid hormone response elements (TREs) located at -322/-317 (TRE1) and -170/-165 (TRE2) were identified, and mutation of either TRE1 or TRE2 abrogated the stimulatory effect of T(3) treatment. Furthermore, two E-box motifs at -911/-906 (E1) and -743/-738 (E2) are involved in the regulation of UCP2 gene expression by sterol regulatory element binding protein isoforms (SREBP)-1a, -1c, and -2. Mutational analysis revealed that the presence of either E1 or E2 is sufficient to mediate activation of UCP2 gene transcription by nuclear active SREBPs. PGC-1alpha coactivates liver X receptor-mediated expression of SREBP-1c as well as dexamethasone-stimulated SREBP-2 expression in INS-1E cells. These transcriptional responses are antagonized by orphan nuclear receptor short heterodimer partner overexpression, which might explain its positive effects on glucose-stimulated insulin secretion in beta-cells overexpressing UCP2. We also provide evidence that despite a lack of sequence homology within the regulatory region, the principal mechanisms regulating UCP2 gene expression are similar in rats and humans, being consistent with a role for UCP2 as a modulator of insulin secretion in humans.

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Triiodothyronine Down-Regulates Thyrotropin-Releasing Hormone (TRH) Synthesis and Decreases pTRH-(160–169) and Insulin Releases from Fetal Rat Islets in Culture1

Cited by 6 publications

References 38 publications

The Thyroid Hormone Triiodothyronine Controls Macrophage Maturation and Functions

The Thyroid Hormone Triiodothyronine Controls Macrophage Maturation and Functions

Molecular Evolution of the Thyrotrophin‐Releasing Hormone Precursor in Vertebrates: Insights From Comparative Genomics

Role of Peroxisome Proliferator-Activated Receptor-γ Coactivator-1α in the Transcriptional Regulation of the Human Uncoupling Protein 2 Gene in INS-1E Cells

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