Overexpression of Metallothionein I/II: A New Feature of Thyroid Follicular Cells in Graves' Disease

Ruiz-Riol, Marta; Martínez-Arconada, María Jesús; Alonso, Núria; Soldevila, Berta; Marchena, D.; Armengol, Manel; Sanmartı́, Anna; Pujol-Borrell, Ricardo; Martínez-Cáceres, Eva

doi:10.1210/jc.2011-1429

Cited by 8 publications

(11 citation statements)

References 32 publications

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“…Previous reports demonstrate that Mt3 mRNA is reduced by thyroxine in the developing rat brain [ 18 ]. Moreover, MT mRNA and protein levels are inducible by thyroid-stimulating hormone (TSH), and their induction is considered a thyroid stress marker of autoimmune diseases [ 52 , 53 ]. Studies in mammals report that ER decreases TH (T3 and/or T4) in serum or plasma [ 54 , 55 ].…”

Section: Discussionmentioning

confidence: 99%

Brain and Hepatic Mt mRNA Is Reduced in Response to Mild Energy Restriction and n-3 Polyunsaturated Fatty Acid Deficiency in Juvenile Rats

Mehus

Picklo

2017

Nutrients

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Metallothioneins (MTs) perform important regulatory and cytoprotective functions in tissues including the brain. While it is known that energy restriction (ER) and dietary n-3 polyunsaturated fatty acid (PUFA) deficiency impact postnatal brain growth and development, little data exist regarding the impact of undernutrition upon MT expression in growing animals. We tested the hypothesis that ER with and without dietary n-3 PUFA deficiency reduces MT expression in juvenile rats. ER rats were individually pair-fed at 75% of the ad libitum (AL) intake of control rats provided diets consisting of either soybean oil (SO) that is α-linolenic acid (ALA; 18:3n-3) sufficient or corn oil (CO; ALA-deficient). Fatty acids (FA) and metal concentrations of liver and brain regions were analyzed. Tissue expression of MTs (Mt1-3) and modulators of MT expression including glucocorticoid receptors (Nr3c1 and Nr3c2) and several mediators of thyroid hormone regulation (Dio1-3, Mct8, Oatp1c1, Thra, and Thrb) were measured. Plasma corticosterone and triiodothyronine levels were also evaluated. ER, but not metal deficiency, reduced Mt2 expression in the cerebellum (50%) and cerebral cortex (23%). In liver, a reduction in dietary n-3 PUFA reduced Mt1, Mt2, Nr3c1, Mct8, and Thrb. ER elevated Nr3c1, Dio1, and Thrb and reduced Thra in the liver. Given MT’s role in cellular protection, further studies are needed to evaluate whether ER or n-3 PUFA deficiency may leave the juvenile brain and/or liver more susceptible to endogenous or environmental stressors.

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Section: Discussionmentioning

confidence: 99%

Brain and Hepatic Mt mRNA Is Reduced in Response to Mild Energy Restriction and n-3 Polyunsaturated Fatty Acid Deficiency in Juvenile Rats

Mehus

Picklo

2017

Nutrients

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“…Frozen thymus sections (4 mm thick) were stained using an indirect immunofluorescence method, as previously described (21). Briefly, frozen cryosections were air dried, and nonspecific binding was reduced by incubation for 1 h with 1% (w/v) BSA in PBS.…”

Section: Immunofluorescence Analysismentioning

confidence: 99%

Autoimmune Predisposition in Down Syndrome May Result from a Partial Central Tolerance Failure due to Insufficient Intrathymic Expression of AIRE and Peripheral Antigens

Giménez‐Barcons

Casteràs

Armengol

et al. 2014

The Journal of Immunology

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Down syndrome (DS), or trisomy of chromosome 21, is the most common genetic disorder associated with autoimmune diseases. Autoimmune regulator protein (AIRE), a transcription factor located on chromosome 21, plays a crucial role in autoimmunity by regulating promiscuous gene expression (pGE). To investigate if autoimmunity in DS is promoted by the reduction of pGE owing to dysregulation of AIRE, we assessed the expression of AIRE and of several peripheral tissue-restricted Ag genes by quantitative PCR in thymus samples from 19 DS subjects and 21 euploid controls. Strikingly, despite the 21 trisomy, AIRE expression was significantly reduced by 2-fold in DS thymuses compared with controls, which was also confirmed by fluorescent microscopy. Allele-specific quantification of intrathymic AIRE showed that despite its lower expression, the three copies are expressed. More importantly, decreased expression of AIRE was accompanied by a reduction of pGE because expression of tissue-restricted Ags, CHRNA1, GAD1, PLP1, KLK3, SAG, TG, and TSHR, was reduced. Of interest, thyroid dysfunction (10 cases of hypothyroidism and 1 of Graves disease) developed in 11 of 19 (57.9%) of the DS individuals and in none of the 21 controls. The thymuses of these DS individuals contained significantly lower levels of AIRE and thyroglobulin, to which tolerance is typically lost in autoimmune thyroiditis leading to hypothyroidism. Our findings provide strong evidence for the fundamental role of AIRE and pGE, namely, central tolerance, in the predisposition to autoimmunity of DS individuals.

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“…Hu et al [ 58 ] reported that the cardiac-specific overexpression of MT rescues nicotine exposure-induced cardiac contractile dysfunction and fibrosis possibly through the inhibition of ROS accumulation and apoptosis. Ruiz-Riol et al [ 59 ] also reported MTs are small proteins induced by tissue stress that can contribute to the restoration of homeostasis in tissue inflammation, and it was found to be increased in a transcriptomic analysis of Graves disease (GD) glands, which shows that overexpression of MT-I/II is a new feature of thyroid follicular cells in GD. Moreover, Zhou et al [ 60 ] suggested that chronic intermittent hypoxia may lead to aortic damages characterized by oxidative stress and inflammation, and MTs may play a pivotal role in the above pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Propylthiouracil, Perchlorate, and Thyroid-Stimulating Hormone Modulate High Concentrations of Iodide Instigated Mitochondrial Superoxide Production in the Thyroids of Metallothionein I/II Knockout Mice

Wang

Zhang

et al. 2016

Endocrinol Metab

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BackgroundIncreased oxidative stress has been suggested as one of the underlying mechanisms in iodide excess-induced thyroid disease. Metallothioneins (MTs) are regarded as scavengers of reactive oxygen species (ROS) in oxidative stress. Our aim is to investigate the effects of propylthiouracil (PTU), a thyroid peroxidase inhibitor, perchlorate (KClO4), a competitive inhibitor of iodide transport, and thyroid stimulating hormone (TSH) on mitochondrial superoxide production instigated by high concentrations of iodide in the thyroids of MT-I/II knockout (MT-I/II KO) mice.MethodsEight-week-old 129S7/SvEvBrd-Mt1tm1Bri Mt2tm1Bri/J (MT-I/II KO) mice and background-matched wild type (WT) mice were used.ResultsBy using a mitochondrial superoxide indicator (MitoSOX Red), lactate dehydrogenase (LDH) release, and methyl thiazolyl tetrazolium (MTT) assay, we demonstrated that the decreased relative viability and increased LDH release and mitochondrial superoxide production induced by potassium iodide (100 µM) can be relieved by 300 µM PTU, 30 µM KClO4, or 10 U/L TSH in the thyroid cell suspensions of both MT-I/II KO and WT mice (P<0.05). Compared to the WT mice, a significant decrease in the relative viability along with a significant increase in LDH release and mitochondrial superoxide production were detected in MT-I/II KO mice(P<0.05).ConclusionWe concluded that PTU, KClO4, or TSH relieved the mitochondrial oxidative stress induced by high concentrations of iodide in the thyroids of both MT-I/II KO and WT mice. MT-I/II showed antioxidant effects against high concentrations of iodide-induced mitochondrial superoxide production in the thyroid.

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Overexpression of Metallothionein I/II: A New Feature of Thyroid Follicular Cells in Graves' Disease

Abstract: These findings show that MT and HLA class II play very different roles in the autoimmune process by affecting the thyroid gland, thereby pointing to the possible role of MT as a marker of cell stress and homeostasis restoration in GD.

Cited by 8 publications

References 32 publications

Brain and Hepatic Mt mRNA Is Reduced in Response to Mild Energy Restriction and n-3 Polyunsaturated Fatty Acid Deficiency in Juvenile Rats

Brain and Hepatic Mt mRNA Is Reduced in Response to Mild Energy Restriction and n-3 Polyunsaturated Fatty Acid Deficiency in Juvenile Rats

Autoimmune Predisposition in Down Syndrome May Result from a Partial Central Tolerance Failure due to Insufficient Intrathymic Expression of AIRE and Peripheral Antigens

Propylthiouracil, Perchlorate, and Thyroid-Stimulating Hormone Modulate High Concentrations of Iodide Instigated Mitochondrial Superoxide Production in the Thyroids of Metallothionein I/II Knockout Mice

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