Iodide Inhibits Vascular Endothelial Growth Factor-A Expression in Cultured Human Thyroid Follicles
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE12244 | GEO | 2008/08/01
SECONDARY ACCESSION(S): PRJNA113709
REPOSITORIES: GEO
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Project description:Graves’ disease is characterized by goiter, palpitation and exophthalmos (Merseburg’s trias). However, a few patients develop exophthalmos even though their thyroid function is normal, a condition known as euthyroid Graves’ disease (EGD). It remains unknown why these patients remain euthyroid, even though they have potent thyroid-stimulating antibody (TSAb). To investigate whether the immunoglobulins (IgGs) obtained from EGD patients elicit thyroid hormone-releasing activity (THRA), thyroid follicles obtained from Graves’ patients were cultured in agarose-coated culture dishes, and 125I incorporated into the thyroid follicles and organic 125I (mainly de novo-synthesized 125I-T3+125I-T4) released into the culture medium by TSH or purified IgGs were determined as thyroid hormone-releasing activity (THRA). This thyroid follicle culture system allows maintenance of the Wolff-Chaikoff effect, and the expression of mRNA for the sodium-iodide symporter is decreased by high concentrations of iodide (10-6-10-4M) and therapeutic concentrations of amiodarone (1-2microM). hTSH elicited THRA most efficiently at 0.4-10 microU/ml, suggesting that thyroid function is controlled within the normal range of TSH concentration (0.4-4.0 microU/ml). All IgGs obtained from hyperthyroid Graves’ patients elicited THRA equivalent to more than 4.6 microU/ml hTSH. IgGs obtained from EGD patients also had potent THRA, whereas IgGs obtained from normal subjects and Graves’ patients in complete remission had no significant THRA. When thyroid follicles from Graves’ thyroid, into which a number of lymphocytes had infiltrated, were used, only slight THRA was elicited by bTSH or Graves’ IgGs, probably due to inflammatory cytokines produced by immunocompetent cells that could not be separated during gentle centrifugation. Indeed, when thyroid follicles were cultured with autologous intrathyroidal lymphocytes, interleukin-2 completely abolished TSH-induced THRA. When thyroid follicles were cultured with inflammatory cytokines (interleukin-1, tumor-necrosis factor-alpha, or interferon-gamma), each cytokine inhibited TSH-induced THRA in a concentration-dependent manner. These cytokines at lower concentrations synergistically and completely inhibited TSH-induced THRA. Microarray analyses of thyroid follicles cultured with IL-1alpha, TNF-alpha, or INF-gamma revealed decreased expression of mRNAs for TSHR, NIS, TPO and thyroglobulin, accompanied by increased expression of mRNAs for chemokines and cytokines. These findings suggest that IgGs obtained from patients with EGD have potent THRA in vitro, whereas in vivo, these IgGs are unable to elicit biological activity in the thyroid gland. Presumably, immunocompetent cells that infiltrate the thyroid gland produce inflammatory cytokines that synergistically inhibit thyroid function. Since a similar phenomenon may occur in the retroorbital tissues, these patients may develop exophthalmos despite having a normal serum level of TSH. This data will be published in Hyperthyroidism: Etiology, Diagnosis and Treatment (editor-in-chief;Dr.Frank Clumbus,Nova Science Publishers, Inc, New York, USA) Experiment Overall Design: One conditioned experiments: control vs. IL-1 alpha 5ng/ml, cultured for 24 hours; control vs. TNF alpha 20ng/ml, cultured for 24 hours; control vs. IFN gamma 1000U/ml, cultured for 48 hours.
2009-05-01 | E-GEOD-15838 | biostudies-arrayexpress
Project description:Graves’ disease is characterized by goiter, palpitation and exophthalmos (Merseburg’s trias). However, a few patients develop exophthalmos even though their thyroid function is normal, a condition known as euthyroid Graves’ disease (EGD). It remains unknown why these patients remain euthyroid, even though they have potent thyroid-stimulating antibody (TSAb). To investigate whether the immunoglobulins (IgGs) obtained from EGD patients elicit thyroid hormone-releasing activity (THRA), thyroid follicles obtained from Graves’ patients were cultured in agarose-coated culture dishes, and 125I incorporated into the thyroid follicles and organic 125I (mainly de novo-synthesized 125I-T3+125I-T4) released into the culture medium by TSH or purified IgGs were determined as thyroid hormone-releasing activity (THRA). This thyroid follicle culture system allows maintenance of the Wolff-Chaikoff effect, and the expression of mRNA for the sodium-iodide symporter is decreased by high concentrations of iodide (10-6-10-4M) and therapeutic concentrations of amiodarone (1-2microM). hTSH elicited THRA most efficiently at 0.4-10 microU/ml, suggesting that thyroid function is controlled within the normal range of TSH concentration (0.4-4.0 microU/ml). All IgGs obtained from hyperthyroid Graves’ patients elicited THRA equivalent to more than 4.6 microU/ml hTSH. IgGs obtained from EGD patients also had potent THRA, whereas IgGs obtained from normal subjects and Graves’ patients in complete remission had no significant THRA. When thyroid follicles from Graves’ thyroid, into which a number of lymphocytes had infiltrated, were used, only slight THRA was elicited by bTSH or Graves’ IgGs, probably due to inflammatory cytokines produced by immunocompetent cells that could not be separated during gentle centrifugation. Indeed, when thyroid follicles were cultured with autologous intrathyroidal lymphocytes, interleukin-2 completely abolished TSH-induced THRA. When thyroid follicles were cultured with inflammatory cytokines (interleukin-1, tumor-necrosis factor-alpha, or interferon-gamma), each cytokine inhibited TSH-induced THRA in a concentration-dependent manner. These cytokines at lower concentrations synergistically and completely inhibited TSH-induced THRA. Microarray analyses of thyroid follicles cultured with IL-1alpha, TNF-alpha, or INF-gamma revealed decreased expression of mRNAs for TSHR, NIS, TPO and thyroglobulin, accompanied by increased expression of mRNAs for chemokines and cytokines. These findings suggest that IgGs obtained from patients with EGD have potent THRA in vitro, whereas in vivo, these IgGs are unable to elicit biological activity in the thyroid gland. Presumably, immunocompetent cells that infiltrate the thyroid gland produce inflammatory cytokines that synergistically inhibit thyroid function. Since a similar phenomenon may occur in the retroorbital tissues, these patients may develop exophthalmos despite having a normal serum level of TSH. This data will be published in Hyperthyroidism: Etiology, Diagnosis and Treatment (editor-in-chief;Dr.Frank Clumbus,Nova Science Publishers, Inc, New York, USA)
2009-04-28 | GSE15838 | GEO
Project description:Amiodarone reversibly decreases sodium-iodide symporter mRNA expression at therapeutic concentrations and induces antioxidant responses at supraphysiological concentrations in cultured human thyroid follicles Amiodarone, a potent antiarrhythmic agent, is a highly active oxidant, exerting cytotoxic effects on thyrocytes at pharmacological concentrations. Patients receiving amiodarone usually remain euthyroid, but occasionally develop thyroid dysfunction, such as amiodarone-associated hypothyroidism or amiodarone-induced thyrotoxicosis. To elucidate the mechanism by which amiodarone elicits thyroid dysfunction, human thyroid follicles were cultured with TSH and amiodarone at therapeutic (1-2 microM) and pharmacological (10-20microM) concentrations, and the drug-induced effect on whole human gene expression was analyzed by cDNA microarray. Amiodarone at 1-2microM decreased the expression level of the sodium-iodide symporter (NIS) to nearly half, but did not affect genes participating in thyroid hormonogenesis (thyroid peroxidase, thyroglobulin, pendrin, NADPH oxidase). Higher concentrations (10-20 microM) decreased the expression of all these genes, accompanied by increased expression of antioxidant proteins such as heme oxygenase 1 and ferritin. When thyroid follicles obtained from a patient with Graves’ disease who had been treated with amiodarone for 2 months before thyroidectomy were cultured in amiodarone-free medium, TSH-induced thyroid function was intact, suggesting that amiodarone at a maintenance dose did not elicit any cytotoxic effect on thyrocytes. The ultrastructural features of cultured thyroid follicles were compatible with these in vitro findings. These in vitro and ex vivo findings suggest that patients taking maintenance doses of amiodarone usually remain euthyroid, probably due to escape from the Wolff-Chaikoff effect mediated by decreased expression of NIS mRNA. Furthermore, amiodarone is not cytotoxic for thyrocytes at therapeutic concentrations but elicits cytotoxicity through oxidant activity at supra-physiological concentrations. Keywords: Cultured human thyroid follicles
2008-07-19 | GSE12164 | GEO
Project description:Thyroid hormone receptor beta (THRB) is post-translationally modified by small ubiquitin-like modifier (SUMO). To investigate the biological role of THRB sumoylation, we generated a mouse model with a mutation that disrupts sumoylation at lysine 146 (K146Q). The THRB K146Q mutant mice had normal serum thyroxine (T4), markedly elevated serum thyrotropin (TSH) (81-fold above control), and enlargement of both the pituitary and the thyroid gland. The marked elevation in TSH, despite a normal serum T4 concentration, indicated blunted feedback regulation of TSH. TH profuction was 10-fold lower (per mg of thyroid tissue) in mutant mice compared to Wt mice.
2021-02-20 | GSE167105 | GEO
Project description:Thyroid autonomy is a frequent cause of thyrotoxicosis in regions with iodine deficiency. Epidemiological data suggest that the prevalence of thyroid autonomy is not only inversely correlated with the ambient iodine supply, but that iodide may also influence the course of pre-existing thyroid autonomy with possibly different effects on thyroid growth and function. Iodine slows TSH effects on thyroid growth stimulation and this effect is more pronounced in thyrocytes with constitutive cAMP activation i.e. in thyroid autonomy. Iodine induced growth alteration in early stage thyroid autonomy is conferred by induction of apoptosis and G2/M arrest. Transcriptome analysis revealed significant modulation of gene networks relevant to cell adhesion, cadherin signalling and ion binding with more pronounced effects in constitutively active FRTL-5 cells compared to normal FRTL-5 cells. The aim was to study iodide-induced changes in global gene expression in an in vitro model of thyroid autonomy. This model makes use of FRTL-5 cells with stable expression of a constitutively activating TSH receptor mutation or wild type TSHR as a control.
2010-12-01 | E-GEOD-22118 | biostudies-arrayexpress
Project description:We are going to submit a paper entitled “Iodide-induced Chemokines and Genes Related to Immunological Function in Cultured Human Thyroid Follicles” to THYROID
2009-07-14 | GSE16957 | GEO
Project description:Deficiency in Krüppel-like zinc finger transcription factor, GLI-Similar 3 (GLIS3) in humans is associated with the development of congenital hypothyroidism. However, the functions of GLIS3 in the thyroid gland and by what mechanism GLIS3-dysfunction causes hypothyroidism are unknown. In this study, we demonstrate that GLIS3 acts downstream of thyroid stimulating hormone (TSH)/TSHR and is indispensable for TSH/TSHR-mediated induction of thyroid follicular cell proliferation and thyroid hormone biosynthesis. ChIP-Seq and promoter analysis revealed that GLIS3 is critical for the transcriptional activation of several genes required for thyroid hormone biosynthesis, including the iodide transporters Nis and Pds, indicating that these genes are directly regulated by GLIS3. The repression of cell proliferation regulatory genes is due to the inhibition of TSH-mediated activation of the mTORC1/RPS6 pathway as well as direct transcriptional regulation of several cell division-related genes by GLIS3. Consequently, GLIS3-deficiency prevents the development of goiter as well as the induction of inflammatory and fibrotic genes during chronic elevation of circulating TSH. Our study identifies GLIS3 as a new and key regulator of TSH/TSHR-mediated thyroid hormone biosynthesis and proliferation of thyroid follicular cells, and uncovers a mechanism by which GLIS3-deficiency causes congenital hypothyroidism and prevents goiter development.
2017-08-30 | GSE103297 | GEO
Project description:Although viral infection is thought to be associated with subacute thyroiditis and probably with autoimmune thyroid disease, possible changes in thyroid function during the prodromal period of infection or subclinical infection remain largely unknown. Recently, it was shown that pathogen-associated molecular patterns stimulate Toll-like receptors (TLR) and activate innate immune responses by producing type I interferons (IFN). Using a human thyroid follicle culture system, in which de novo synthesized thyroid hormones are released into the culture medium under physiological concentrations of hTSH, we studied the effects of polyinosinic-polycytidylic acid (Poly(I:C)), a chemical analog of viral double-stranded RNA (dsRNA), on TSH-induced thyroid function. Thyrocytes expressed ligands for dsRNA (TLR 3, CD14, and RIG-1) comparable to the TSH receptor. DNA microarray and real-time PCR analyses revealed that dsRNA increased the expression of mRNA for TLR3, IFN-g, interferon-regulating factors, proinflammatory cytokines, and class I MHC, whereas genes associated with thyroid hormonogenesis (NIS, peroxidase, deiodinases) were suppressed. In accordance to these data, Poly(I:C) suppressed TSH-induced 125I uptake and hormone synthesis dose-dependently, accompanied by a decrease in the ratio of 125I-T3/125I-T4 released into the culture medium, whereas peptidoglycan, lipopolysaccharides, or unmethylated CpG DNA, ligands for TLR2, TLR4, and TLR9, respectively, had no significant effect. These inhibitory effects of Poly(I:C) were not blocked by a neutralizing antibody against TLR3 and an anti-IFN alpha/beta receptor antibody. These in vitro findings suggest that when thyrocytes are infected with certain viruses, dsRNA formed intracellularly in thyrocytes may be a cause for thyroid dysfunction, leading to development of autoimmune thyroiditis. This data was published in Endocrinology, vol.148, 3226-3235, 2007. Keywords: Cultured human thyroid follicles
2008-07-18 | GSE12154 | GEO
Project description:Thyroid autonomy is a frequent cause of thyrotoxicosis in regions with iodine deficiency. Epidemiological data suggest that the prevalence of thyroid autonomy is not only inversely correlated with the ambient iodine supply, but that iodide may also influence the course of pre-existing thyroid autonomy with possibly different effects on thyroid growth and function. Iodine slows TSH effects on thyroid growth stimulation and this effect is more pronounced in thyrocytes with constitutive cAMP activation i.e. in thyroid autonomy. Iodine induced growth alteration in early stage thyroid autonomy is conferred by induction of apoptosis and G2/M arrest. Transcriptome analysis revealed significant modulation of gene networks relevant to cell adhesion, cadherin signalling and ion binding with more pronounced effects in constitutively active FRTL-5 cells compared to normal FRTL-5 cells.
2010-12-01 | GSE22118 | GEO
Project description:Although viral infection is thought to be associated with subacute thyroiditis and probably with autoimmune thyroid disease, possible changes in thyroid function during the prodromal period of infection or subclinical infection remain largely unknown. Recently, it was shown that pathogen-associated molecular patterns stimulate Toll-like receptors (TLR) and activate innate immune responses by producing type I interferons (IFN). Using a human thyroid follicle culture system, in which de novo synthesized thyroid hormones are released into the culture medium under physiological concentrations of hTSH, we studied the effects of polyinosinic-polycytidylic acid (Poly(I:C)), a chemical analog of viral double-stranded RNA (dsRNA), on TSH-induced thyroid function. Thyrocytes expressed ligands for dsRNA (TLR 3, CD14, and RIG-1) comparable to the TSH receptor. DNA microarray and real-time PCR analyses revealed that dsRNA increased the expression of mRNA for TLR3, IFN-g, interferon-regulating factors, proinflammatory cytokines, and class I MHC, whereas genes associated with thyroid hormonogenesis (NIS, peroxidase, deiodinases) were suppressed. In accordance to these data, Poly(I:C) suppressed TSH-induced 125I uptake and hormone synthesis dose-dependently, accompanied by a decrease in the ratio of 125I-T3/125I-T4 released into the culture medium, whereas peptidoglycan, lipopolysaccharides, or unmethylated CpG DNA, ligands for TLR2, TLR4, and TLR9, respectively, had no significant effect. These inhibitory effects of Poly(I:C) were not blocked by a neutralizing antibody against TLR3 and an anti-IFN alpha/beta receptor antibody. These in vitro findings suggest that when thyrocytes are infected with certain viruses, dsRNA formed intracellularly in thyrocytes may be a cause for thyroid dysfunction, leading to development of autoimmune thyroiditis. This data was published in Endocrinology, vol.148, 3226-3235, 2007. Experiment Overall Design: Two conditioned experimets, control vs. double-stranded RNA (polyI-C), cultured for 6
2008-10-21 | E-GEOD-12154 | biostudies-arrayexpress