The sodium iodide symporter gene and its regulation by cytokines found in autoimmunity

Ajjan, Ramzi; Watson, P.; Findlay, Charles W.; Metcalfe, Russell; Crisp, M.; Ludgate, Marian; Weetman, A. P.

doi:10.1677/joe.0.1580351

Cited by 105 publications

(85 citation statements)

References 32 publications

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“…INFg has a variety of effects on human thyrocytes in culture; it inhibits TSH-induced TH and Tg secretion (Nagayama et al 1987, Kung et al 1992 as well as Tg mRNA expression (Sato et al 1990), TSH-induced TPO expression ) and the TSH-and cAMPinduced upregulation of TSH receptors on the thyrocyte (Nishikawa et al 1993). IFNg also inhibits the TSH-induced increase in NIS expression in rat FTRL-5 cells resulting in diminished iodide uptake (Ajjan et al 1998). Interestingly, overexpression of IFNg in thyroid cells in a transgenic mouse leads to primary hypothyroidism mainly due to a big decrease in NIS mRNA and protein expression (Caturegli et al 2000).…”

Section: The Effect Of Cytokines On Th Synthesismentioning

confidence: 99%

The molecular basis of the non-thyroidal illness syndrome

Vries¹,

Fliers²,

Boelen³

2015

Journal of Endocrinology

153

116

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The 'sick euthyroid syndrome' or 'non-thyroidal illness syndrome' (NTIS) occurs in a large proportion of hospitalized patients and comprises a variety of alterations in the hypothalamus-pituitary-thyroid (HPT) axis that are observed during illness. One of the hallmarks of NTIS is decreased thyroid hormone (TH) serum concentrations, often viewed as an adaptive mechanism to save energy. Downregulation of hypophysiotropic TRH neurons in the paraventricular nucleus of the hypothalamus and of TSH production in the pituitary gland points to disturbed negative feedback regulation during illness. In addition to these alterations in the central component of the HPT axis, changes in TH metabolism occur in a variety of TH target tissues during NTIS, dependent on the timing, nature and severity of the illness. Cytokines, released during illness, are known to affect a variety of genes involved in TH metabolism and are therefore considered a major determinant of NTIS. The availability of in vivo and in vitro models for NTIS has elucidated part of the mechanisms involved in the sometimes paradoxical changes in the HPT axis and TH responsive tissues. However, the pathogenesis of NTIS is still incompletely understood. This review focusses on the molecular mechanisms involved in the tissue changes in TH metabolism and discusses the gaps that still require further research.

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Section: The Effect Of Cytokines On Th Synthesismentioning

confidence: 99%

The molecular basis of the non-thyroidal illness syndrome

Vries¹,

Fliers²,

Boelen³

2015

Journal of Endocrinology

153

116

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“…The molecular characterization of the regulation of iodide transport has become possible since the cloning of the NIS gene. Indeed, in recent years, the regulation of NIS expression has been extensively studied, at both mRNA and protein levels, by using either in vivo or in vitro experimental models (Table 2) (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). In primary cultured human thyrocytes, TSH and forskolin upregulate NIS gene expression and NIS protein abundance, with 2.5-to 2.7-fold and 2.4-to 2.7-fold increases after 24 h and 48 h respectively (15).…”

Section: Iodide Concentration and Utilization By Thyroid Cells And Imentioning

confidence: 99%

Sodium/iodide symporter: a key transport system in thyroid cancer cell metabolism

Filetti¹,

Bidart

Arturi³

et al. 1999

European Journal of Endocrinology

252

144

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The recent cloning of the gene encoding the sodium/iodide symporter (NIS) has enabled better characterization of the molecular mechanisms underlying iodide transport, thus opening the way to clarifying its role in thyroid diseases. Several studies, at both the mRNA and the protein expression levels, have demonstrated that TSH, the primary regulator of iodide uptake, upregulates NIS gene expression and NIS protein abundance, both in vitro and in vivo. However, other factors, including iodide, retinoic acid, transforming growth factor-b, interleukin-1a and tumour necrosis factor a, may participate in the regulation of NIS expression. Investigation of NIS mRNA expression in different thyroid tissues has revealed increased levels of expression in Graves' disease and toxic adenomas, whereas a reduction or loss of NIS transcript was detected in differentiated thyroid carcinomas, despite the expression of other specific thyroid markers. NIS mRNA was also detected in non-thyroid tissues able to concentrate radioiodine, including salivary glands, stomach, thymus and breast.The production of specific antibodies against the NIS has facilitated study of the expression of the symporter protein. Despite of the presence of high levels of human (h)NIS mRNA, normal thyroid glands exhibit a heterogeneous expression of NIS protein, limited to the basolateral membrane of the thyrocytes. By immunohistochemistry, staining of hNIS protein was stronger in Graves' and toxic adenomas and reduced in thyroid carcinomas.Measurement of iodide uptake by thyroid cancer cells is the cornerstone of the follow-up and treatment of patients with thyroid cancer. However, radioiodide uptake is found only in about 67% of patients with persistent or recurrent disease. Several studies have demonstrated a decrease in or a loss of NIS expression in primary human thyroid carcinomas, and immunohistochemical studies have confirmed this considerably decreased expression of the NIS protein in thyroid cancer tissues, suggesting that the low expression of NIS may represent an early abnormality in the pathway of thyroid cell transformation, rather than being a consequence of cancer progression.The relationship between radioiodine uptake and NIS expression by thyroid cancer cells require further study. New strategies, based on manipulation of NIS expression, to obtain NIS gene reactivation or for use as NIS gene therapy in the treatment of radiosensitive cancer, are also being investigated. European Journal of Endocrinology 141 443-457 Role of iodine in thyroid physiology and pathophysiology Iodine in thyroid physiologyIodine represents an essential element in thyroid physiology, being a critical component of thyroxine and tri-iodothyronine molecules, and a key regulator of thyroid gland function. Thus dietary iodide supply influences the functional activity of the thyroid gland, iodine deficiency being the main cause of endemic goiter. Furthermore, iodine directly modulates thyroid sensitivity to thyroid-stimulating hormone (TSH), and intrathyroidal iodin...

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“…There is conflicting evidence on the effect of IFN-γ on thyroidal NIS expression. Whereas [64] reported that IFN-γ had no effect on iodide accumulation or NIS mRNA levels, [71] observed that IFN-γ at a high concentration (1000 U/ml) down-regulated TSH-stimulated NIS mRNA levels. The latter results were confirmed in an in vivo study by Caturegli et al (2000) that reported a severe impairment of thyroid function and a loss of typical follicular structure combined with down-regulation of NIS expression and activity in transgenic mice expressing IFN-γ in the thyroid [73].…”

Section: Other Modulators Of Nis Functionmentioning

confidence: 95%

“…The thyroidal effects of cytokines (tumour necrosis factor alpha (TNF-α) and beta (TNF-β), interferon-γ (IFN-γ), interleukins 1-alpha (IL-1α), 1-beta (IL-1β), −6 (IL-6) and transforming growth factor-beta (TGF-β)) have been evaluated in FRTL-5 cells. and reported that TNF-α inhibited TSH-stimulated NIS mRNA expression in FRTL-5 cells [68,71]. In addition, Pekary et al (1998) reported that TNF-induced inhibition of NIS expression was mediated by the activation of sphingomyelinase, an enzyme that converts sphingomyelin to ceramide in the plasma membrane [27].…”

Section: Other Modulators Of Nis Functionmentioning

confidence: 99%

The Biology of the Sodium Iodide Symporter and its Potential for Targeted Gene Delivery

Hingorani¹

2010

CCDT

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The sodium iodide symporter (NIS) is responsible for thyroidal, salivary, gastric, intestinal and mammary iodide uptake. It was first cloned from the rat in 1996 and shortly thereafter from human and mouse tissue. In the intervening years, we have learned a great deal about the biology of NIS. Detailed knowledge of its genomic structure, transcriptional and post-transcriptional regulation and pharmacological modulation has underpinned the selection of NIS as an exciting approach for targeted gene delivery. A number of in vitro and in vivo studies have demonstrated the potential of using NIS gene therapy as a means of delivering highly conformal radiation doses selectively to tumours. This strategy is particularly attractive because it can be used with both diagnostic ( 99m Tc, 125 I, 124 I) and therapeutic ( 131 I, 186 Re, 188 Re, 211 At) radioisotopes and it lends itself to incorporation with standard treatment modalities, such as radiotherapy or chemoradiotherapy. In this article, we review the biology of NIS and discuss its development for gene therapy.

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The sodium iodide symporter gene and its regulation by cytokines found in autoimmunity

Cited by 105 publications

References 32 publications

The molecular basis of the non-thyroidal illness syndrome

The molecular basis of the non-thyroidal illness syndrome

Sodium/iodide symporter: a key transport system in thyroid cancer cell metabolism

The Biology of the Sodium Iodide Symporter and its Potential for Targeted Gene Delivery

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