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Abstract
The aims of the present study were to determine the influence of brief subclinical hypothyroidism on the isoforms of serum thyrotropin (TSH) and to examine the net charge of TSH in different metabolic states. Sera were obtained from euthyroid subjects (n=7) and from patients with subclinical hypothyroidism (n=8) before and 30 min after the intravenous administration of 200 μg thyrotropin-releasing hormone (TRH). The TSH from human pituitary extracts (IRP 68/38), basal and TRH-stimulated serum TSH was immunoconcentrated and further analysed by isoelectric focusing (IEF) and lentil lectin affinity chromatography. TSH immunoreactivity was determined in each specimen or fraction with an automated highly sensitive chemiluminometric TSH assay. We found that basal TSH in subclinical hypothyroidism, and TRH-released TSH in euthyroidism and in subclinical hypothyroidism is distributed in a similar neutral to acidic pattern, which significantly differs from the more alkaline to neutral isoform pattern of intrapituitary TSH (P<0·05). IEF analysis of pituitary standard TSH revealed 3 major peaks (pI values 7·5; 6·6; 5·8) whereas in most euthyroid or subclinically hypothyroid subjects 5 peaks were found. Lentil lectin affinity chromatography revealed that TRH-released TSH in euthyroid subjects has more core fucose residues than TSH from patients with subclinical hypothyroidism (64·6 ±6·7 vs 12·5 ±2·7%, P<0·0001).
Thus pituitary standard TSH seems to be less mature material than circulating TSH. Perhaps no alteration in the IEF pattern of TSH was detected during early hypothyroidism because sialylation of TSH was increasing as sulfatation was decreasing. Nevertheless, a change in the core fucose content of TSH was detectable by lentil analysis.
Journal of Endocrinology (1995) 144, 561–567
Department of Endocrinology, Erasme University Hospital, Free University of Brussels, Route de Lennik, 808, 1070 Brussels, Belgium
Stazione Zoologica Anton Dohrn,
Department of Cellular and Molecular Biology and Pathology, University of Naples ‘Federico II’, 80121 Naples, Italy
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Department of Endocrinology, Erasme University Hospital, Free University of Brussels, Route de Lennik, 808, 1070 Brussels, Belgium
Stazione Zoologica Anton Dohrn,
Department of Cellular and Molecular Biology and Pathology, University of Naples ‘Federico II’, 80121 Naples, Italy
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Department of Endocrinology, Erasme University Hospital, Free University of Brussels, Route de Lennik, 808, 1070 Brussels, Belgium
Stazione Zoologica Anton Dohrn,
Department of Cellular and Molecular Biology and Pathology, University of Naples ‘Federico II’, 80121 Naples, Italy
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Department of Endocrinology, Erasme University Hospital, Free University of Brussels, Route de Lennik, 808, 1070 Brussels, Belgium
Stazione Zoologica Anton Dohrn,
Department of Cellular and Molecular Biology and Pathology, University of Naples ‘Federico II’, 80121 Naples, Italy
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Department of Endocrinology, Erasme University Hospital, Free University of Brussels, Route de Lennik, 808, 1070 Brussels, Belgium
Stazione Zoologica Anton Dohrn,
Department of Cellular and Molecular Biology and Pathology, University of Naples ‘Federico II’, 80121 Naples, Italy
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Department of Endocrinology, Erasme University Hospital, Free University of Brussels, Route de Lennik, 808, 1070 Brussels, Belgium
Stazione Zoologica Anton Dohrn,
Department of Cellular and Molecular Biology and Pathology, University of Naples ‘Federico II’, 80121 Naples, Italy
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Department of Endocrinology, Erasme University Hospital, Free University of Brussels, Route de Lennik, 808, 1070 Brussels, Belgium
Stazione Zoologica Anton Dohrn,
Department of Cellular and Molecular Biology and Pathology, University of Naples ‘Federico II’, 80121 Naples, Italy
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Department of Endocrinology, Erasme University Hospital, Free University of Brussels, Route de Lennik, 808, 1070 Brussels, Belgium
Stazione Zoologica Anton Dohrn,
Department of Cellular and Molecular Biology and Pathology, University of Naples ‘Federico II’, 80121 Naples, Italy
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(NIS), Tg and the thyroid-stimulating hormone (TSH) receptor (Tshr), are expressed just after the thyroid precursor cells have completed their migration from the primitive pharynx and reached their final location around the trachea ( Lazzaro et al
Aquatic Ecology and Toxicology, Department of Zoology, University of Heidelberg, D-69120 Heidelberg, Germany
Department of Endocrinology, Institute of Biology, Humboldt University, D-10115 Berlin, Germany
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Aquatic Ecology and Toxicology, Department of Zoology, University of Heidelberg, D-69120 Heidelberg, Germany
Department of Endocrinology, Institute of Biology, Humboldt University, D-10115 Berlin, Germany
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Aquatic Ecology and Toxicology, Department of Zoology, University of Heidelberg, D-69120 Heidelberg, Germany
Department of Endocrinology, Institute of Biology, Humboldt University, D-10115 Berlin, Germany
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Aquatic Ecology and Toxicology, Department of Zoology, University of Heidelberg, D-69120 Heidelberg, Germany
Department of Endocrinology, Institute of Biology, Humboldt University, D-10115 Berlin, Germany
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Aquatic Ecology and Toxicology, Department of Zoology, University of Heidelberg, D-69120 Heidelberg, Germany
Department of Endocrinology, Institute of Biology, Humboldt University, D-10115 Berlin, Germany
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Aquatic Ecology and Toxicology, Department of Zoology, University of Heidelberg, D-69120 Heidelberg, Germany
Department of Endocrinology, Institute of Biology, Humboldt University, D-10115 Berlin, Germany
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Aquatic Ecology and Toxicology, Department of Zoology, University of Heidelberg, D-69120 Heidelberg, Germany
Department of Endocrinology, Institute of Biology, Humboldt University, D-10115 Berlin, Germany
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Aquatic Ecology and Toxicology, Department of Zoology, University of Heidelberg, D-69120 Heidelberg, Germany
Department of Endocrinology, Institute of Biology, Humboldt University, D-10115 Berlin, Germany
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, Dohan et al. 2003 ). Together, these studies demonstrated that thyroid-stimulating hormone (TSH) stimulates NIS activity via up-regulation of NIS mRNA and protein expression in thyroid follicular cells ( Kogai et al. 1997 , Saito et al. 1997 a
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ABSTRACT
A screen of a range of bacteria normally found in gut flora identified eight with the ability to bind TSH specifically. These included the previously reported Yersinia enterocolitica, Gram-positive, Gramnegative, pathogenic and commensal organisms. Eleven preparations of TSH-receptor autoantibodies strongly able to displace 125I-labelled TSH from the mammalian TSH receptor differed in their ability to displace the tracer from binding to bacterial extracts. None could displace the tracer from E. coli 06–1, four displaced 125I-labelled TSH from E. coli V21/1 and five displaced the tracer from Y. enterocolitica. Of those immunoglobulin preparations which did react with the bacterial protein, their apparent potency compared with that of TSH in displacing tracer from bacterial binders was an order of magnitude greater than with the mammalian receptor. This is consistent with the autoantibodies having a relatively better fit with the bacterial antigen than with the receptor when compared with TSH. The bacterial-binding activity and mammalian receptor-binding activities in each of two samples co-chromatographed on a Remazol yellow GGL–Sepharose affinity column strongly indicated that the same immunoglobulin species reacts with both antigens. These results are consistent with the proposal that a bacterial protein is the primary immunogen for the TSH-receptor antibodies in at least some patients with Graves' disease.
Journal of Endocrinology (1989) 121, 571–577
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Leptin is a circulating hormone secreted by adipose tIssue which acts as a signal to the central nervous system where it regulates energy homeostasis and neuroendocrine processes. Although leptin modulates the secretion of several pituitary hormones, no information is available regarding a direct action of pituitary products on leptin release. However, it has been pointed out that leptin and TSH have a coordinated pulsatility in plasma. In order to test a direct action of TSH on in vitro leptin secretion, a systematic study of organ cultures of human omental adipose tIssue was performed in samples obtained at surgery from 34 patients of both sexes during elective abdominal surgery. TSH powerfully stimulated leptin secretion by human adipose tIssue in vitro. In contrast, prolactin, ACTH, FSH and LH were devoid of action. These results suggest that leptin and the thyroid axis maintain a complex and dual relationship and open the possibility that plasmatic changes in TSH may contribute to the regulation of leptin pulses.
Department of Molecular Medicine, Division of Immunology, Atomic Bomb Disease Institute
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Introduction Graves' disease is a thyroid-specific autoimmune disease characterized by overproduction of thyroid hormones and thyroid enlargement by agonistic anti-TSH receptor (TSHR) autoantibody. Graves'-like hyperthyroidism can be experimentally
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The thyroid-stimulating hormone (TSH) binds to a receptor which activates adenylate cyclase and elevates cAMP concentration. In addition, effects of TSH on intracellular calcium and inositol phosphate accumulation have been reported. However, the mechanism of TSH-stimulated accumulation of inositol phosphates and elevation of calcium levels is unresolved. Previous work from this laboratory has shown TSH to cause acute transient increases in intracellular calcium in pig, human and FR TL-5 rat thyroid cells as well as in cell transfected with the human TSH receptor (JPO9 cells) in some (but not all) experiments. The aim of this study was to investigate the variability of the calcium response to TSH in JPO9 cells to learn more about the nature of this calcium signal induction. Calcium responses to TSH were determined using the fluorochrome fura-2 in both monolayers of adherent cells and adherent single cells. The responses to a single addition and to repetitive additions of TSH were compared. We also determined the cAMP response to TSH using these two protocols of TSH addition. Our data show that, whereas the cAMP response to TSH is highly predictable and consistent and does not require multiple exposures to TSH, cells were unlikely to respond to TSH with an increase in calcium unless they received multiple challenges with the hormone. A single addition of 10 mU/ml TSH failed to increase calcium in any of 40 single cells examined and in only 4 of 15 monolayers of cells (27%) examined; in contrast, 10 of 12 monolayers eventually responded with an increase in calcium after multiple exposure to TSH and 18 of 67 single cells. Similar data were obtained whether calcium was measured in single cells or in populations of cells. We also demonstrated cooperativity between an adenosine derivative, N6-(L-2-phenylisopropyl)adenosine, and TSH such that their co-administration resulted in a consistent and marked elevation in calcium levels not achieved with either agonist alone. In summary, we suggest that the coupling between the TSH receptor and the intracellular signalling system that leads to activation of intracellular calcium in JPO9 cells requires repetitive stimulation or the influence of other agonists, in contrast with the coupling between the TSH receptor and activation of the adenylate cyclase enzyme.
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ABSTRACT
Mitotic and labelling indices were studied in the thyroid follicular cells of the male rat within the first hour after a single injection of TSH or TSH vehicle, using the metaphase arrest agent vincristine sulphate. There was a significant increase in metaphase index over control values 5, 15, 30 and 60 min after injection of TSH. There was no significant change in the tritiated thymidine labelling index in TSH-treated rats in comparison with vehicle-injected controls. None of the metaphase figures was labelled, showing that G2 in this tissue is longer than 2 h.
Journal of Endocrinology (1989) 121, 27–30
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Abstract
Inositol 1,4,5-trisphosphate (InsP3) 3-kinase phosphorylates the Ca2+-mobilizing second messenger InsP3 to inositol 1,3,4,5-tetrakisphosphate (InsP4). InsP3 5-phosphatase dephosphorylates InsP3 to inositol 1,4-bisphosphate (InsP2). We compared the effects of TSH added to a culture of FRTL-5 thyroid cells on the activity of InsP3 5-phosphatase and InsP3 3-kinase. InsP3 3-kinase activity was decreased at a physiological concentration of TSH. Inhibition of this activity started after 3 h of incubation with TSH and was maximal after 24 h. In contrast, InsP3 5-phosphatase activity was not affected by TSH under the same conditions. The inhibitory effect of TSH on InsP3 3-kinase was characterized as follows: a) inhibition of activity was mimicked by both dibutyryl cyclic AMP and forskolin; b) activity obtained by mixing lysates of TSH-stimulated and non-stimulated cells was the sum of each activity measured separately; c) inhibition persisted after a crude lysate of TSH-stimulated cells had been subjected to SDS/polyacrylamide gel electrophoresis and the extraction of InsP3 3-kinase activity. The data suggest that TSH reduced the activity of InsP3 3-kinase in FRTL-5 cells either by a phosphorylation/dephosphorylation mechanism, or by affecting expression of the enzyme.
Journal of Endocrinology (1995) 144, 527–532
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Leptin has been shown to stimulate the hypothalamus-pituitary-thyroid axis in fasting rodents; however, its role in thyroid axis regulation under physiological conditions is still under investigation. Here it was investigated in freely fed rats whether leptin modulates thyrotroph function in vivo and whether leptin has direct pituitary effects on TSH release. Since leptin is produced in the pituitary, the possibility was also investigated that leptin may be a local regulator of TSH release. TSH was measured by specific RIA. Freely fed adult rats 2 h after being injected with a single s.c. injection of 8 microg leptin/100 g body weight showed a 2-fold increase in serum TSH (P<0.05). Hemi-pituitary explants incubated with 10(-9) and 10(-7) M leptin for 2 h showed a reduced TSH release of 40 and 50% respectively (P<0.05). Conversely, incubation of hemi-pituitary explants with antiserum against leptin, aiming to block the action of locally produced leptin, resulted in higher TSH release (45%, P<0.05). In conclusion, also in the fed state, leptin has an acute stimulatory effect on TSH release in vivo, acting probably at the hypothalamus. However, the direct pituitary effect of leptin is inhibitory and data also provide evidence that in the rat pituitary leptin may act as an autocrine/paracrine inhibitor of TSH release.
