Evidence for a role of the type III-iodothyronine deiodinase in the regulation of 3,5,3'-triiodothyronine content in the human central nervous system

Department of Endocrinology and Metabolism, University of Pisa, Italy.
European Journal of Endocrinology (Impact Factor: 4.07). 07/2001; 144(6):577-83. DOI: 10.1530/eje.0.1440577
Source: PubMed


Thyroid hormone is essential for maintaining normal neurological functions both during development and in adult life. Type III-iodothyronine deiodinase (D3) degrades thyroid hormones by converting thyroxine and 3,5,3'-triiodothyroinine (T3) to inactive metabolites. A regional expression of D3 activity has been observed in the human central nervous system (CNS), and a critical role for D3 has been suggested in the regulation of local T3 content in concert with other enzymes.
This study was undertaken to further characterize D3 activity in human CNS and to understand its role in the local regulation of T3 content.
Autoptic specimens from various areas of human CNS were obtained 6--27 h postmortem from 14 donors who died from cardiovascular accident, neoplastic disease or infectious disease. D3 was determined by measuring the conversion of T3 to 3,3'-diiodothyronine. The T3 content was measured by radioimmunoassay in ethanol extracts, using a specific antiserum.
High levels of D3 activity were observed in hippocampus and temporal cortex, lower levels being found in the thalamus, hypothalamus, midbrain cerebellum, parietal and frontal cortex, and brain stem. An inverse relationship between D3 activity and T3 content in these areas was demonstrated.
We have concluded that D3 contributes to the local regulation of T3 content in the human CNS.

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    • "Astrocytes also express D3, a selenoprotein that is responsible for the degradation of thyroid hormone in the brain (Courtin et al. 1986, Ramauge et al. 1996). The opposing activities of D2 and D3 are believed to maintain brain T3 levels (Santini et al. 2001). In astrocytes, D3 is induced by multiple pathways, including cAMP, TPA, FGF, thyroid hormones and retinoic acid (Courtin et al. 1991, Esfandiari et al. 1994a). "
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    ABSTRACT: Astrocyte cells clearly play a role in neural development, but nowadays their total action is seen as a far wider one. Recent findings consider them as stem cells, involved in the control of most facets of functional neural networks. Astrocytes play a central role in thyroid hormone metabolism in the brain, being the principal transporters of thyroxine from the blood, responsible for its conversion to 3,5,3'-triiodothyronine and hence supplying the neural tissues with the biologically active form of the hormone. Specific thyroid hormone transporters play an essential role in this regulatory system. The presence of thyroid hormone receptors has been demonstrated in cultured astrocytes. Furthermore, thyroid hormone regulates several aspects of astrocyte differentiation and maturation, including the production of extracellular matrix proteins and growth factors, and thus controls neuronal growth and neuritogenesis. Therefore, astrocytes are currently suggested as important mediators of thyroid hormone in neuronal development.
    Journal of Endocrinology 06/2006; 189(2):189-97. DOI:10.1677/joe.1.06680 · 3.72 Impact Factor
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    • "D1 activity is undetectable in human fetal and adult cerebral cortices (Campos-Barros et al. 1996, Chan et al. 2002) and is unlikely to play a significant role in the human brain. In contrast, D2 and D3 enzymes, with K m values in the nanomolar range (Visser et al. 1983, 1988, Salvatore et al. 1996), are thought to be crucial in the homeostatic regulation of intracellular T 3 concentrations (Bates et al. 1999) especially in the brain (Santini et al. 2001), where approximately 80% of T 3 is derived locally through D2 activity (Crantz et al. 1982). "
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    ABSTRACT: N-TERA-2 cl/D1 (NT2) cells, a human embryonal cell line with characteristics of central nervous system precursor cells, were utilised to study thyroid hormone action during early neuronal growth and differentiation. Undifferentiated NT2 cells expressed mRNAs encoding thyroid hormone receptors (TRs) alpha1, alpha2 and beta1, iodothyronine deiodinases types 2 (D2) and 3 (D3) (which act as the pre-receptor regulators), and the thyroid hormone-responsive genes myelin basic protein (MBP) and neuroendocrine specific protein A (NSP-A). When terminally differentiated into post-mitotic neurons (hNT), TRalpha1 and TRbeta1 mRNA expression was decreased by 74% (P=0.05) and 95% (P<0.0001) respectively, while NSP-A mRNA increased 7-fold (P<0.05). However, mRNAs encoding TRalpha2, D2, D3 and MBP did not alter significantly upon neuronal differentiation and neither did activities of D2 and D3. With increasing 3,5,3'-triiodothyronine (T(3)) concentrations, TRbeta1 mRNA expression in cultured NT2 cells increased 2-fold at 10 nM T(3) and 1.3-fold at 100 nM T(3) (P<0.05) compared with that in T(3)-free media but no change was seen with T(3) treatment of hNT cells. D3 mRNA expression in NT2 cells also increased 3-fold at 10 nM T(3) (P=0.01) and 2.4-fold at 100 nM T(3) (P<0.05) compared with control, but there was no change in D3 enzyme activity. In contrast there was a 20% reduction in D3 mRNA expression in hNT cells at 10 nM T(3) (P<0.05) compared with control, with accompanying reductions in D3 activity with increasing T(3) concentrations (P<0.05). There was no significant change in the expression of the TRalpha isoforms, D2, MBP and NSP-A with increasing T(3) concentrations in either NT2 or hNT cells. Undifferentiated NT2 and differentiated hNT cells show differing patterns of T(3)-responsiveness, suggesting that there are different regulatory factors operating within these cell types.
    Journal of Endocrinology 08/2003; 178(1):159-67. · 3.72 Impact Factor
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    ABSTRACT: The concentrations of the iodothyronine metabolites T(4), T(3), 3,5-diiodothyronine (3,5-T(2)), 3,3'-diiodothyronine (3,3'-T(2)), reverse T(3) (rT(3)), 3,3'-T(2) sulfate (3,3'T(2)S), and T(3) sulfate (T(3)S) were measured in 12 regions of the brain, the pituitary gland, and liver in adult male rats. Quantification of iodothyronine was performed by RIA following a newly developed method of purification and separation by HPLC. 3,5-T(2), 3,3'-T(2), rT(3) and T(2)S were detectable in the low femtomolar range (20-200 fmol/g) in most areas of the rat brain. T(3)S was detectable only in the hypothalamus. The concentrations of T(3) and T(4) were approximately 20- to 60-fold higher, ranging between 1 and 6 pmol/g. There was a significant negative correlation between the activities of inner-ring deiodinase and T(3) concentrations across brain areas. In the liver, 3,5-T(2), rT(3), and T(3)S were measurable in the low femtomolar range, whereas 3,3'-T(2) and 3,3'T(2)S were not detectable. 3,5-T(2) and 3,3'-T(2) were not detectable in mitochondrial fractions of the brain regions. Tissue concentrations of 3,5-T(2) exhibited a circadian variation closely parallel to those of T(3) in the brain regions and liver. T(3) was not a substrate for outer-ring deiodination under different experimental conditions; thus, it remains unclear which substrate(s) and enzyme(s) are involved in the production of 3,5-T(2). These results indicate that five iodothyronine metabolites other than T(3) and T(4) are detectable in the low femtomolar range in the rat brain and/or liver. The physiological implications of this finding are discussed.
    Endocrinology 06/2002; 143(5):1789-800. DOI:10.1210/en.143.5.1789 · 4.50 Impact Factor
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