Regulation of Thyroid Peroxidase and Thyroglobulin Gene Expression by Thyrotropin in Cultured Human Thyroid Cells

Nagayama, Yuji; Yamashita, Shunichi; Hirayu, Hideshi; Izumi, Motomori; Uga, Tatsuro; Ishikawa, Naofumi; Ito, Kunihiko; Nagataki, Shigenobu

doi:10.1210/jcem-68-6-1155

Cited by 56 publications

(18 citation statements)

References 26 publications

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“…It has been demonstrated that the effects of TSH are largely mediated by the cAMP-dependent pathway and the relevance of the cAMP cascade in thyroid follicular cells has been well established (Dumont et al 1992, Roger et al 1995, Dremier et al 1997. The expression of several thyroidspecific genes such as Tg (Avvedimento et al 1984, Santisteban et al 1987, TPO (Magnusson & Rapoport 1985, Nagayama et al 1989, TSHR (Kohn et al 1995) and NIS , Ohmori et al 1998, Ohno et al 1999, Spitzweg et al 1999 has been shown to be modulated by TSH/cAMP. While in the case of the TSHR a CRE site has been shown to play an important role (Ikuyama et al 1992, Shimura et al 1993, and in the NIS upstream enhancer element a CRE-like site has been recently identified (Ohno et al 1999), the situation is more complicated for the Tg promoter.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have led to the conclusion that TSH regulates the expression of the Tg gene by determining its rate of transcription (Avvedimento et al 1984, Van Heuverswyn et al 1984, Santisteban et al 1987. A number of in vitro studies, in which cultured thyrocytes were used, have shown that lack of TSH leads to a drastic reduction in Tg mRNA and that re-addition of TSH is able to reactivate Tg transcription (Chebath et al 1979, Tosta et al 1983, Nagayama et al 1989. In vivo studies in the rat also suggested that TSH controls Tg gene transcription via the interaction with its receptor on thyrocytes, and that cAMP is a physiological mediator of this effect (Van Heuverswyn et al 1984.…”

Section: Introductionmentioning

confidence: 99%

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Hormonal control of the transcription factor Pax8 and its role in the regulation of thyroglobulin gene expression in thyroid cells

Mascia¹,

Nitsch²,

Lauro³

et al. 2002

Journal of Endocrinology

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The transcription factor Pax8 plays an important role in the expression of the differentiated phenotype of thyroid follicular cells. It has recently been shown that Pax8 is necessary for thyroglobulin (Tg) gene expression in the fully differentiated rat thyroid cell line PC. We have used the PC model system to investigate the role of Pax8 as a mediator of TSH regulation of Tg gene expression. We have demonstrated that Pax8 expression, as well as Tg expression, is severely reduced in cells grown in the absence of hormones and serum. The re-addition of TSH or forskolin to the culture medium is able to restore to wild-type levels the expression of both Pax8 and Tg. We have determined that the action of TSH/forskolin on Pax8 is at the transcriptional level. However, the re-expression of Pax8 can be observed several hours before that of Tg, suggesting that either another factor is needed or that Pax8 itself must be post-translationally modified by a newly synthesized protein to become active. To distinguish between these two possibilities we have stably transfected into PC cells an exogenous Pax8 that is expressed independently of TSH. Our results indicate that in these cells the Tg promoter is still dependent on TSH despite the constitutive presence of Pax8. Furthermore, we also show that in this condition Tg gene transcription requires de novo protein synthesis. In conclusion, TSH regulates the expression of Pax8 at a transcriptional level and also regulates the activity of Pax8 by controlling the expression of one or more as yet unknown factors.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hormonal control of the transcription factor Pax8 and its role in the regulation of thyroglobulin gene expression in thyroid cells

Mascia¹,

Nitsch²,

Lauro³

et al. 2002

Journal of Endocrinology

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“…Since TSH increases the expression of thyroid autoantigen, microsomal antigen (thyroid peroxidase) [16,17] and thyroglobulin [18,19], the TSH increase induced by IFN may amplify immune responses in autoimmune thyroid disease, and thyroid dysfunction may develop.…”

Section: Discussionmentioning

confidence: 99%

Effect of Interferon-Beta on Thyroid Function in Patients of Chronic Hepatitis C without Preexisting Autoimmune Thyroid Disease.

et al. 1996

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Abstract. The effect of interferon-beta (IFN-fl) on thyroid function was studied in patients with chronic hepatitis who had no preexisting thyroid disease. Eleven patients (9 males and 2 females) aged 20 to 65 years, with a mean age of 47.7 ± 13.5 years, were treated with 6 million units of IFN-fl intravenously every day for 8 weeks. During IFN-13 administration (4th to 8th week of treatment), both serum free thyroxine (FT4) and free triiodothyronine (FT3) concentrations decreased significantly (P<0.0005 and P<0.05, respectively): FT4, 1.37 ± 0.17 to 1.09 ± 0.12 ng/dl, and FT3, 3.71 ± 0.45 to 3.28 ± 0.34 pg/ml. On the other hand, serum TSH increased significantly from a baseline of 1.70 ± 0.82 to 3.34 ± 1.98 jiU/ml during IFN-13 administration (P<0.005). Four to eight weeks after cessation of treatment, the mean serum FT4 concentration was similar to that during IFN-f administration (1.04 ± 0.14 ng/dl), but mean serum FT3 and TSH concentrations returned to pre-treatment levels (FT3, 3.57 ± 0.42 pg/ml and TSH, 1.60 ± 0.84 ,uU/ml). Both reverse T3 and thyroglobulin were essentially unchanged. Tests for anti-thyroglobulin and anti-microsomal antibodies were negative in all the patients. These results indicate that IFN-f3 may inhibit thyroid function in patients without preexisting thyroid disease irrespective of humoral immune responses.

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“…IFN␥ suppresses Tg expression in FRTL-5 cells (28,29) and human thyrocytes (30), where IFN␥ also impairs Tg secretion (5,31). To determine whether IFN␥ altered Tg expression in WRT cells, immunostaining and Western blotting experiments were performed.…”

Section: Ifn␥ Represses Camp-induced Tg Expression and Dna Synthesismentioning

confidence: 99%

“…TSH stimulates the expression of thyroid-specific genes, including the TSH receptor (TSHR) (reviewed in Ref. 1), thyroglobulin (Tg) (2)(3)(4)(5), thyroid peroxidase (5, 6), iodothyronine 5-deiodinase (7), and the sodium-iodide symporter (8,9). Cytokines, including interferon-␥ (IFN␥), interleukin-1␤ (IL-1␤), and tumor necrosis factor-␣, are believed to participate in the development and progression of thyroid autoimmunity.…”

mentioning

confidence: 99%

Differential Effects of Acute and Chronic Exposure to Interferon-γ on Cyclic Adenosine 3′,5′-Monophosphate Response Element-Regulated Gene Expression1

et al. 2000

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TSH stimulates proliferation and maintains differentiated function in thyroid follicular cells. The mitogenic activity and the stimulatory effects of TSH on thyroid-specific gene expression are impaired by interferon-␥ (IFN␥); however, the mechanisms for these effects have not been elucidated in detail. We examined the effects of IFN␥ on acute responses to TSH in rat thyroid cells. IFN␥ did not impair TSH-stimulated p70/p85 ribosomal protein S6 kinase (p70/ p85s6k) activity or cAMP response element (CRE)-regulated gene expression, although it inhibited DNA synthesis and thyroglobulin expression, effects measured over a more prolonged time course than those on kinase activity and reporter gene expression. Unexpectedly, when cells were chronically exposed to IFN␥, CRE-lacZ promoter activity was decreased, whereas other cAMP-mediated signals, such as p70/p85s6k activity and CRE-binding protein phosphorylation, were unaffected. Activating protein-1-regulated promoters were also impaired by IFN␥ treatment, but with kinetics that differed from those of CRE-regulated promoters. Neither acute nor chronic treatment with interleukin-1␤ impaired cAMP signaling, indicating that the effects of IFN␥ are specific. These studies identify CRE-and activating protein-1-regulated promoters as targets of IFN␥ in thyroid cells and fibroblasts. IFN␥-mediated inhibition of these promoters, in addition to those containing thyroid-specific transcription factor-1-binding sites, may contribute to the profound effects of IFN␥ on thyroid cells. (Endocrinology 141: 606 -614, 2000) T SH COORDINATELY regulates proliferation and differentiated function in thyroid follicular cells. TSH stimulates the expression of thyroid-specific genes, including the TSH receptor (TSHR) (reviewed in Ref. 1), thyroglobulin (Tg) (2-5), thyroid peroxidase (5, 6), iodothyronine 5-deiodinase (7), and the sodium-iodide symporter (8, 9). Cytokines, including interferon-␥ (IFN␥), interleukin-1␤ (IL-1␤), and tumor necrosis factor-␣, are believed to participate in the development and progression of thyroid autoimmunity. IFN␥ increases the autoantigenicity of thyrocytes by upregulating MHC class I expression (10) and by inducing aberrant expression of MHC class II antigens (11-17). Moreover, the expression of several genes under regulatory control by TSH is inhibited by IFN␥. In turn, TSH impairs IFN␥-stimulated Fas expression (18). In addition to opposing effects on gene expression, TSH and IFN␥ exert differential effects on proliferation, where IFN␥ has been shown to inhibit TSH-stimulated proliferation (12,19,20).Thyroid-specific transcription factor-1 (TITF-1; previously termed TTF-1) (21) has been identified as one molecular target of IFN␥ in FRTL-5 cells where IFN␥ decreases TITF-1 DNA-binding activity on the TSHR promoter (22). In human thyroid cells, IFN␥ activates a nuclear protein that binds to the Tg promoter and diminishes Tg expression (23). Given the multitude of the effects of IFN␥ on thyroid cells, it seems likely that there are additional mechan...

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Regulation of Thyroid Peroxidase and Thyroglobulin Gene Expression by Thyrotropin in Cultured Human Thyroid Cells

Cited by 56 publications

References 26 publications

Hormonal control of the transcription factor Pax8 and its role in the regulation of thyroglobulin gene expression in thyroid cells

Hormonal control of the transcription factor Pax8 and its role in the regulation of thyroglobulin gene expression in thyroid cells

Effect of Interferon-Beta on Thyroid Function in Patients of Chronic Hepatitis C without Preexisting Autoimmune Thyroid Disease.

Differential Effects of Acute and Chronic Exposure to Interferon-γ on Cyclic Adenosine 3′,5′-Monophosphate Response Element-Regulated Gene Expression1

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