Inhibition of TSH-stimulated thyroid hormone release and potentiation of TRH-stimulated TSH release by indomethacin in perifusion systems of rat thyroids and pituitaries

Using indomethacin (Ind), a prostaglandin synthesis inhibitor, in vivo experiments in rats and in vitro experiments with perifusion systems of rat thyroids and pituitaries were conducted. After 35 days of intragastric infusion of Ind, serum TSH levels were markedly increased, the thyroid was swollen and, as a consequence, T3 and T4 levels were normal. The T3 release from perifused rat thyroids under continuous stimulation with 10 mU/ml TSH was inhibited significantly (p less than 0.01) by 1.0 X 10(-6) M Ind. On the other hand, the TSH release from perifused rat pituitaries under TRH stimulation was enhanced conspicuously by Ind. It was concluded that Ind decelerated thyroid hormone release from the thyroid and accelerated TSH release from the pituitary in perifusion systems.     

Hormonal control of manganese transport in the mouse thyroid.

The present study deals with a possible mechanism controlling the transport of manganese (Mn), an essential trace element, from the circulation to the thyroid. Mice were pretreated with propylthiouracil (PTU) or triiodothyronine (T3), and a measurement of the thyroid:serum concentration ratio (T/S) of radioactive manganese (54Mn) was carried out. The T/S of 54Mn was greatly enhanced by PTU, but reduced by T3. Several methods were used to demonstrate that the T/S of 54Mn depends upon the level of thyroid-stimulating hormone (TSH) in the serum. First, bovine TSH was injected into mice; an increase in the T/S resulted. Secondly, serum thyroxine and T3 levels measured by radioimmunoassay (RIA) suggested that PTU produced an increase in serum TSH and T3 a decrease. However, direct measurement of mouse TSH by RIA for rat TSH failed to produce proof of any changes in TSH level, owing to poor cross-reactivity. Taking all the information into account, it is concluded that Mn-transport into the thyroid is controlled by the thyroid state.     

Release of 3,5,3′-triiodothyronine,thyroxine and thyroglobulin from TSH-stimulated mouse thyroids in the perifusion system

Summary We established a perifusion system using mouse thyroid glands. In this system, TSH increased the release of T₃ and T₄ significantly, and the response of thyroglobulin to TSH was delayed in comparison with that of T₃ and T₄.     

Hormonal control of manganese transport in the mouse thyroid

The present study deals with a possible mechanism controlling the transport of manganese (Mn), an essential trace element, from the circulation to the thyroid. Mice were pretreated with propylthiouracil (PTU) or triiodothyronine (T₃), and a measurement of the thyroid:serum concentration ratio (T/S) of radioactive manganese (⁵⁴Mn) was carried out. The T/S of⁵⁴Mn was greatly enhanced by PTU, but reduced by T₃. Several methods were used to demonstrate that the T/S of⁵⁴Mn depends upon the level of thyroid-stimulating hormone (TSH) in the serum. First, bovine TSH was injected into mice; an increase in the T/S resulted. Secondly, serum thyroxine and T₃ levels measured by radioimmunoassay (RIA) suggested that PTU produced an increase in serum TSH and T₃ a decrease. However, direct measurement of mouse TSH by RIA for rat TSH failed to produce proof of any changes in TSH level, owing to poor cross-reactivity. Taking all the information into account, it is concluded that Mn-transport into the thyroid is controlled by the thyroid state.     

Respective roles of circulating T4 and T3 in control of TSH secretion in severely iodide-deficient rats

Summary After a 6-month iodide deficiency, Wistar male rats were submitted to a normal iodine diet (20 and 50 g of¹²⁷I daily). Plasma T₃, T₄ and TSH were determined by RIA from 0 to 140 days of iodide refeeding. A highly significant correlation was found between plasma TSH and T₄ concentrations, but not between plasma TSH and T₃ levels. These data suggest that an increase in plasma T₃ alone, up to the normal value, is not able to inhibit TSH secretion. It is only when a certain plasma T₄ concentration is also reached, resulting in further T₃ formation through deiodination, that TSH secretion is inhibited.Dedicated to the memory of Prof. C. Simon.This work was supported by grants from the CNRS (Equipe de Recherche Associée no 234) and from the INSERM (A.T.P. 49.77.8).Acknowledgments. The authors wish to thank Mrs M. Chartier for valuable technical assistance. They are indebted to the rat pituitary distribution programme of NIAMDD, NIH, Bethesda, for their gift of rat TSH reagents.     

Correlation between 3′,5′, c-AMP levels and thyrotropin in separated rat pituitary thyrotropic cells

Summary The correlation between 3,5, c-AMP levels, TSH content and secretion of separated thyrotropic cells was studied. Incubation of the separated cells with 1, 10 and 100 ng of TRH does not change the 3,5, c-AMP levels, despite the significant rises of the TSH level. Dibutyryl c-AMP causes rise in TSH content, with no indication of its secretion. PGE₂ 10^–5 increased 3, 5, c-AMP levels with no change in the content or secretion of TSH in separated thyrotropic cells.     

Inhibition of TSH-stimulated thyroid hormone release and potentiation of TRH-stimulated TSH release by indomethacin in perifusion systems of rat thyroids and pituitaries

Summary Using indomethacin (Ind), a prostaglandin, synthesis inhibitor, in vivo experiments in rats and in vitro experiments with perifusion systems of rat thyroids and pituitaries were conducted. After 35 days of intragastric infusion of Ind, serum TSH levels were markedly increased, the thyroid was swollen and, as a consequence, T₃ and T₄ levels were normal. The T₃ release from perifused rat thyroids under continuous stimulation with 10 mU/ml TSH was inhibited significantly (p<0.01) by 1.0×10^–6 M Ind. On the other hand, the TSH release from perifused rat pituitaries under TRH stimulation was enhanced conspicuously by Ind. It was concluded that Ind decelerated thyroid hormone release from the thyroid and accelerated TSH release from the pituitary in perifusion systems.     

The TSH receptor and its role in thyroid disease

The thyrotropin (TSH) receptor plays a preeminent role in thyroid physiology and disease. TSH, acting through the TSH receptor, is the major stimulator of thyroid cell growth, differentiation and function. In Graves' disease, the TSH receptor is the target of stimulating antibodies that cause hyperthyroidism. Although still a topic of debate, the TSH receptor has been implicated in the pathogenesis of the endocrine ophthalmopathy associated with Graves' disease. Blocking antibodies against the TSH receptor are involved in the development of hypothyroidism in a subset of patients with autoimmune hypothyroidism. Transplacental passage of stimulating or blocking TSH receptor antibodies from a mother with autoimmune thyroid disease may result in transient hyper- or hypothyroidism in early infancy. During pregnancy, the placental hormone human choriogonadotropin (hCG) can cause gestational hyperthyroidism through cross-reaction with the TSH receptor. Gestational hyperthyroidism may also be involved in the pathogenesis of hyperemesis gravidarum. Trophoblast tumors secreting hCG are a rare cause of hyperthyroidism. Somatic activating mutations of the TSH receptor have been identified as a molecular cause of toxic adenomas, whereas activating mutations in the germline give rise to nonautoimmune familial hyperthyroidism or sporadic congenital hyperthyroidism. These gain-of-function mutations are dominant, and one mutated allele is sufficient to result in disease. Inactivating germline mutations of both TSH receptor alleles lead to variable degrees of resistance to TSH, encompassing a spectrum ranging from euthyroid hyperthyrotropinemia to overt hypothyroidism with thyroid hypoplasia. Received 31 January 2001; received after revision 3 April 2001; accepted 3 April 2001     

Correlation between 3',5', c-AMP levels and thyrotropin in separated rat pituitary thyrotropic cells.

The correlation between 3',5', c-AMP levels, TSH content and secretion of separated thyrotropic cells was studied. Incubation of the separated cells with 1, 10 and 100 ng of TRH does not change the 3',5',c-AMP levels, despite the significant rises of the TSH level. Dibutyryl c-AMP causes rise in TSH content, with no indication of its secretion. PGE2 10(-5) increased 3'5',c-AMP levels with no change in the content or secretion of TSH in separated thyrotropic cells.     

On the time course of thyrotropin suppression by high doses of thyroid hormones

Summary Basal and stimulated TSH decreased progressively. Basal TSH was suppressed below the detection limit of 0.4 U/ml after 74 h in 2 of the T₃ and all of the T₄ treated indiduals. At this time, in both groups 3 individuals could be significantly stimulated by TRH (about 5% of the pretreatment stimulation). There was no significant difference in the time course of suppression obtained by T₃ or T₄, though plasma T₃ levels in the T₄ treated group were considerably lower.Supported by the Deutsche ForschungsgemeinschaftThe excellent technical assistance of MissM. Knöpfle, MissU. Neun and Mr.G. Magin is gratefully acknowledged.     

Immunoactive TSH in the amniotic fluid of the rat

Summary Amniotic fluid was obtained from 19-day-old rat fetuses by aspiration. Pooled samples measured at 4 different dilutions demonstrated parallelism with standard rat TSH. It is concluded that rat amniotic fluid has TSH immunoactivity.This work was supported by Hong Kong University Research Grant No. 335/034/5727.The authors wish to acknowledge with thanks the gift of rat TSH RIA kit from Dr A. F. Parlow and the Rat Pituitary Programme of NIAMDD.     

Reciprocal changes in serum free thyroxine fraction and thyrotropin level after administration of thiocyanate to rats

Summary The administration of thiocyanate to rats caused a significant increase of serum free thyroxine fraction, which coincided with the significant decrease of TSH level. The other components (AFT₄, T₄, T₃) in serum at this time were decreased or unchanged. The finding suggests the role of free thyroxine fraction in feed-back regulation of TSH secretion.Acknowledgment. We thank Dr A. Parlow and the NIAMDD, Rat Pituitary Hormone Distribution Program, for material for rat TSH immunoassay; Dr J. Nauman (Inst. Postgrad. Med., Warsaw, Poland) for T₃ antibody, and to Ing. J. Sadlo, Mrs M. t'astná and Miss R Fajkoová for technical assistance.     

Thyroid activity in response to some gonadal steroids in methallibure-treatedHeteropneustes fossilis (Bloch)

Summary Methallibure treatment is as effective as hypophysectomy in reducing thyroid activity inH. fossilis. Sex steroids (TP and EB) administration restored thyroid activity in methallibure-treated females to normal level, but failed to elicit any response in males. This drug seems to block TSH secretion and thyroid hormone synthesis inH. fossilis.Financial assistance in the form of SRF from ICAR, New Delhi to one of us (R.B.R.), gift of methallibure from ICI Ltd., UK and TSH from NIH, USA, to T.P.S. are gratefully acknowledged.     

Plasma triiodothyronine,thyroxine and thyrotrophin levels in germfree rats

Summary Plasma T₃, T₄ and TSH levels in developing germfree rats were high, low and normal as compared with those in conventional counterparts. The high T₃/T₄ ratio in germfree rat plasma was lowered by cholestyramine feeding.This work was supported in part by a grant from the Imanaga Foundation, Nagoya, Japan.     

Increased responsiveness of the thyroid to thyrotropin by pretreatment with thyroid hormones in intact mice

Zusammenfassung Im McKenzie-Bioassay für TSH, LATS oder TRH steigt die Ansprechbarkeit der Mäuseschilddrüse auf TSH an, wenn die Tiere 3 Tage lang mit Schilddrüsenhormon vorbehandelt werden. Die Mengen von Schilddrüsenhormon sind dabei so zu wählen, dass sie zu einer partiellen Substitution führen.     

Changes in the T4/T3 molar ratio following thyrotropin releasing hormone injection in cattle.

The injection of thyrotropin releasing hormone into cattle resulted in a rapid decrease in the T4/T3 molar ratio. 2 breeds of cattle, Shorthorn and Africander Cross were studied. The decrease in the T4/T3 molar ratio was significantly greater in the Shorthorn breed. It is concluded that acute stimulation of the thyroid gland with TRH results in enhanced release of both T3 and T4 and that T3 is discharged more rapidly than T4.     

<Emphasis Type="Italic">Yersinia pseudotuberculosis</Emphasis> supports Th17 differentiation and limits de novo regulatory T cell induction by directly interfering with T cell receptor signaling

Adaptive immunity critically contributes to control acute infection with enteropathogenic Yersinia pseudotuberculosis; however, the role of CD4⁺ T cell subsets in establishing infection and allowing pathogen persistence remains elusive. Here, we assessed the modulatory capacity of Y. pseudotuberculosis on CD4⁺ T cell differentiation. Using in vivo assays, we report that infection with Y. pseudotuberculosis resulted in enhanced priming of IL-17-producing T cells (Th17 cells), whereas induction of Foxp3⁺ regulatory T cells (Tregs) was severely disrupted in gut-draining mesenteric lymph nodes (mLNs), in line with altered frequencies of tolerogenic and proinflammatory dendritic cell (DC) subsets within mLNs. Additionally, by using a DC-free in vitro system, we could demonstrate that Y. pseudotuberculosis can directly modulate T cell receptor (TCR) downstream signaling within naïve CD4⁺ T cells and Tregs via injection of effector molecules through the type III secretion system, thereby affecting their functional properties. Importantly, modulation of naïve CD4⁺ T cells by Y. pseudotuberculosis resulted in an enhanced Th17 differentiation and decreased induction of Foxp3⁺ Tregs in vitro. These findings shed light to the adjustment of the Th17-Treg axis in response to acute Y. pseudotuberculosis infection and highlight the direct modulation of CD4⁺ T cell subsets by altering their TCR downstream signaling.     

Action of TSH on nuclear ADP-ribosylation in dog thyroid slices

Summary Treatment of dog thyroid slices with thyrotropin (TSH) results in an increase in ADP-ribosylation in nuclei isolated thereafter. This increase is time-dependent and is observed with concentrations of TSH eliciting physiological responses. The technique described here does not involve permeabilization of cell membranes, thereby avoiding artefacts which could arise from hypotonic shock. Cyclic AMP mimicked the stimulatory action of TSH.     

Influence of age on the plasma hormonal iodine response to thyrotropin injection in young calves]

The influence of age upon the increase in plasma hormonal iodine level following an intravenous injection of bovine TSH (0.2 USP units/kg) was studied in young jersey calves. The response to TSH increased between birth and the 7th day, then decreased regularly until the end of the third month. Reasons for these variations are discussed according to some results obtained following TSH injections.     

Effects of photoperiod, temperature and testosterone-treatment on plasma T3 and T4 levels in the Djungarian hamster, Phodopus sungorus

The effects of photoperiod, temperature and testosterone treatment on plasma T3 and T4 levels were investigated in the Djungarian hamster. Plasma T3 level was affected by temperature (25 degrees C less than 7 degrees C) but not by photoperiod. Plasma T4 level was affected by photoperiod (short day less than long day) at 25 degrees C. Administration of testosterone increased plasma T4 level under short photoperiod at 25 degrees C. Thus, higher plasma T4 level under long photoperiod at 25 degrees C might be induced by testosterone.