Effect of thyroid hormones on delayed type hypersensitivity reaction

The effect of long term administration of thyroid hormones and its deprivation on delayed type hypersensitivity (DTH) reaction to 2-4 dinitrochlorobenzene (DNCB) was studied. Animals were either pre-treated with thyroid hormones (T3 or T4) for 15 days and then subjected to DNCB skin test or the animals received thyroid hormones and simultaneously subjected to DNCB skin test. In both the cases DTH reaction was found to be increased significantly. When DNCB skin test was performed in the thyroidectomized animals, DNCB skin reaction was significantly decreased and the reaction was restored to normal following supplementation of thyroid hormones to the thyroidectomized animals. TLC and ALC were increased significantly following hormone treatment and thyroidectomized animals. TLC hand, induced significant depression in the count which was restored by hormone administration to the thyroidectomized animals.     

Chronic stress influences the immune system through the thyroid axis

The aim of the present work was to analyze the effect of chronic stress on thyroid axis and its influence on the immune response. For this purpose a murine model of chronic stress was developed to evaluate and to correlate thyroid hormone levels with humoral alloimmune response. Results show a reduction in serum levels of thyroid hormones, specially a significant decrease in serum levels of triiodotyronine (T3) in stressed animals. On the other hand, alloimmunization was not able to induce an early increment in T3 and thyroxine (T4) levels as it was previously reported in normal animals. In addition, lower titers of alloantibodies were obtained in animals under stress conditions as compared to normal mice. The sustitutive T4 treatment in stressed animals increased significantly alloantibody production as well as the early increment in thyroid hormones after antigenic challenge. These findings suggest that chronic stress induces an alteration of the function of thyroid axis that alters the immune response.     

Developmentally regulated thyroid hormone distributor proteins in marsupials, a reptile, and fish

Thyroid hormones are essential for vertebrate development. There is a characteristic rise in thyroid hormone levels in blood during critical periods of thyroid hormone-regulated development. Thyroid hormones are lipophilic compounds, which readily partition from an aqueous environment into a lipid environment. Thyroid hormone distributor proteins are required to ensure adequate distribution of thyroid hormones, throughout the aqueous environment of the blood, and to counteract the avid partitioning of thyroid hormones into the lipid environment of cell membranes. In human blood, these proteins are albumin, transthyretin and thyroxine-binding globulin. We analyzed the developmental profile of thyroid hormone distributor proteins in serum from a representative of each order of marsupials (M. eugenii; S.crassicaudata), a reptile (C. porosus), in two species of salmonoid fishes (S. salar; O. tshawytsch), and throughout a calendar year for sea bream (S. aurata). We demonstrated that during development, these animals have a thyroid hormone distributor protein present in their blood which is not present in the adult blood. At least in mammals, this additional protein has higher affinity for thyroid hormones than the thyroid hormone distributor proteins in the blood of the adult. In fish, reptile and polyprotodont marsupial, this protein was transthyretin. In a diprotodont marsupial, it was thyroxine-binding globulin. We propose an hypothesis that an augmented thyroid hormone distributor protein network contributes to the rise in total thyroid hormone levels in the blood during development.     

甲状腺激素对小鼠免疫功能的调节作用

正常昆明种成年小鼠每天给予一定量的甲状腺激素可使其抗体生成能力、淋巴细胞转化能力、迟发型超敏反应和巨噬细胞的吞噬功能明显增强,外周血成熟 T 细胞数量亦明显增加。而每天给予抗甲状腺药物则使其抗体生成能力、淋巴细胞转化能力和迟发型超敏反应明显降低。切除甲状腺亦使抗体生成能力下降。这些结果提示甲状腺激素参与免疫功能的生理性调节。     

Manipulating thyroid status alters endoplasmic reticulum calcium homeostasis in rat cerebellum

Thyroid-related hormones regulate the efficiency and expression of sarco-endoplasmic reticulum calcium ATPases in cardiac and skeletal muscle. However, little is known about the relationship between thyroid hormones and calcium (Ca2+) homeostasis in the brain. It is hypothesized that manipulating rat thyroid hormone levels would induce significant brain Ca2+ adaptations consistent with clinical findings. Adult male Sprague-Dawley rats were assigned to one of three treatment groups for 28 days: control, hypothyroid (6-n-propyl-2-thiouracil (PTU), an inhibitor of thyroxine (T4) synthesis), and hyperthyroid (T4). Throughout, rats were given weekly behavioral tests. Ca2+ accumulation decreased in the cerebellum in both hyper- and hypothyroid animals. This was specific to different ER pools of calcium with regional heterogeneity in the response to thyroid hormone manipulation. Behavioral tasks demonstrated sensitivity to thyroid manipulation, and corresponded to alterations in calcium homeostasis. Ca2+ accumulation heterogeneity in chronic hyper- and hypothyroid animals potentially explains clinical manifestations of altered thyroid status.     

Response of thyroid hormones in peripheral and thyroid venous blood to TRH administration in man

Thyroid vein and cubital vein samples were collected simultaneously in 6 moderately hypercalcemic patients and 1 eucalcemic hypothyroid patient, and thyroid hormones were measured in the serum in the basal state, as well as 30 and 60 min after intravenous administration of TRH. No gradient was detectable between peripheral and thyroid blood in the case of T4, and no significant changes were observed following TRH. The levels of T3 were higher in the thyroid venous effluent than in the periphery and a marked increase occurred following TRH. Serum thyroglobulin also increased following TRH, but there was no peripheral vs. thyroid gradient. Calcitonin demonstrated a marked positive gradient in the thyroid vein compared to the periphery, but no change was observed following TRH. It is concluded that the patterns of response of individual thyroid hormones reflect differences in their secretion and, specifically, that intrathyroid conversion of T4 to T3 occurs during the thyroid hormone secretion.     

The effects of age, season and geographic region on thyroid hormones in Steller sea lions (Eumetopias jubatus)

The purpose of this study was to investigate thyroid hormone concentrations, thyroxine (T4) and triiodothyronine (T3), in order to determine basal levels in Steller sea lions of different ages and over seasons. Serum concentrations of total T4 were highest in Steller sea lions followed by total T3 concentrations. Concentrations of free T4 and free T3 were three to four orders of magnitude lower. Concentrations for all four thyroid hormone measurements tended to a lower level as animals matured beyond the neonatal stage. When thyroid hormones from captive sea lions were evaluated across seasons, all thyroid hormones were highest in the July to September period. When compared across the geographic range, animals in southeast Alaska tended to have lower thyroid hormone levels, while the Steller sea lions west of Prince William Sound and animals from the Russian Far East had significantly higher concentrations. Significant inter-annual differences in concentrations were also observed across the geographic range. With an understanding of the basic changes in thyroid hormone concentrations, changes in plane of nutrition or life history states (i.e. fasting, pregnancy or lactation) can now be evaluated for their effect on the overall health of this endangered species.     

The role of the thyroid in the development of Mauthner's neuron

Summary Although the normal postmetamorphic atrophy of the giant neurons of Mauthner in anuran amphibians has been attributed to the direct or indirect action of thyroid hormone, the administration of exogenous thyroxin to Rana pipiens larvae appears to facilitate growth of the neuron rather than inhibit it. In the present investigation, Rana pipiens embryos were surgically thyroidectomized. In the absence of the thyroid, metamorphosis never occurred, and hind limb development was arrested at larval stages VI–VIII. However, these animals continued their growth and often exceed their controls in overall size. Mauthner cells of thyroidectomized larvae have nuclei of significantly smaller size than their controls. The observations are consonant with the view that thyroid hormones play an important positive role in the growth and maintenance of Mauthner's cell. It is further indicated that the growth of Mauthner's neuron is more dependent upon the titer of thyroid hormone in the blood than it is upon age, brain size, tail motor influences, or the state of the lateral line system.Dedicated to Professor Berta Scharrer on her 60th birthday. This study was supported by Grants NB-04555, IGS-98 and 5 T 1-GM-102 from the U.S.P.H.S.I am pleased to acknowledge the excellent technical assistance of Mrs. Celia Grubman.     

Salmonella Typhi sense host neuroendocrine stress hormones and release the toxin haemolysin E

Salmonella enterica serovar Typhi (S. typhi) causes typhoid fever. We show that exposure of S. typhi to neuroendocrine stress hormones results in haemolysis, which is associated with the release of haemolysin E in membrane vesicles. This effect is attributed to increased expression of the small RNA micA and RNA chaperone Hfq, with concomitant downregulation of outer membrane protein A. Deletion of micA or the two-component signal-transduction system, CpxAR, abolishes the phenotype. The hormone response is inhibited by the β-blocker propranolol. We provide mechanistic insights into the basis of neuroendocrine hormone-mediated haemolysis by S. typhi, increasing our understanding of inter-kingdom signalling.     

Seroepidemiology of enteric fever and brucellosis in a developing country

The seroepidemiology of infection due to S. typhi and Brucella spp. in a sub-tropical, developing country of the Middle East was investigated in 130 children of age less than 1 to 15 years, 117 young adults (16-30 years) and in a further 40 adults (greater than 30 years) using an agglutination test to detect antibodies to of S. typhi, B. abortus and B. melitensis. Only 4.5% of the children's and adult's sera respectively showed the presence of antibodies to both O and H antigens of S. typhi with reciprocal titers greater than or equal to 80. Prevalence rates of 11.6%, 11.3% respectively in children and adults of antibodies to B. abortus with reciprocal titers greater than or equal to 80 and similarly 13.1%, 12.4% to B. melitensis were found. The usefulness of a single Widal test to diagnose enteric fever in a non-endemic area and the agglutination test in the diagnosis of brucellosis in an endemic area was investigated. Of 244 patients with suspected enteric fever, the sera of 100 showed reciprocal antibody titers 80 to both O and H antigens and included in these were 8 patients with concurrent culture positivity. Among 138 children and adults with suspected brucellosis, 29 culture proven cases where serologically confirmed and a further 90 were detected serologically. The sera of all the culture proven cases exhibited antibody reciprocal titer greater than or equal to 640. A similar antibody response was noted in seventy-two of the culture negative cases diagnosed serologically for brucellosis. In culture proven, cases B. melitensis was the isolate. Comparative evaluation indicated the potential usefulness of the Rose Bengal Antigen Slide Agglutination Test (Brucelloside Test) as a screening test in the serodiagnosis of human brucellosis.     

Role of thyroid hormones in the normal and glucocorticosteroid hormone-induced evolution of carbamoyl-phosphate synthase (ammonia) activity in axolotl liver.

1. In axolotl liver, the activity of carbamoyl-phosphate synthase (ammonia), expressed per mg liver protein, decreases to a minimum at 5 months of age, then increases to a maximum at 8 months of age which is followed by a decrease again. The initial decrease between 3 and 5 months of age appears to be largely due to an increase in non-carbamoyl-phosphate synthase protein and the following increase between 5 and 8 months of age to a relative increase of carbamoyl-phosphate synthase protein. 2. Treatment of the animals with triiodothyronine causes an increase in carbamoyl-phosphate synthase activity, the extent of which is dependent upon hormone concentration and age of the animal. After 8 months of age no increase of enzyme occurs upon thyroid hormone treatment, although metamorphosis occurs. 3. Glucocorticosteroid hormones stimulate carbamoyl-phosphate synthase activity 2-to 3-fold in animals older than 6 months. However, in animals younger than 6 months, low concentrations of thyroid hormone, insufficient to induce metamorphosis, are necessary as permissive agents. 4. The stimulatory effects of high concentrations of thyroid hormones (T3) on carbamoyl-phosphate synthase appear to be mediated via a stimulatory effect on glucocorticosteroid biosynthesis. 5. The natural rise in enzyme activity between 5 and 8 months of age seems to be due to a rise in the concentration of circulating glucocorticosteroid hormones.     

Thyroid hormone stimulates protein synthesis in the cardiomyocyte by activating the Akt-mTOR and p70S6K pathways

Thyroid hormones affect cardiac growth and phenotype; however, the mechanisms by which the hormones induce cardiomyocyte hypertrophy remain uncharacterized. Tri-iodo-L-thyronine (T3) treatment of cultured cardiomyocytes for 24 h resulted in a 41 +/- 5% (p < 0.001) increase in [(3)H]leucine incorporation into total cellular protein. This response was abrogated by the phosphatidylinositol 3-kinase (PI3K) inhibitor, wortmannin. Co-immunoprecipitation studies showed a direct interaction of cytosol-localized thyroid hormone receptor TRalpha1 and the p85alpha subunit of PI3K. T3 treatment rapidly increased PI3K activity by 52 +/- 3% (p < 0.005), which resulted in increased phosphorylation of downstream kinases Akt and mammalian target of rapamycin (mTOR). This effect was abrogated by pretreatment with wortmannin or LY294002. Phosphorylation of p70(S6K), a known target of mTOR, occurred rapidly following T3 treatment and was inhibited by rapamycin and wortmannin. In contrast, phosphorylation of the p85 variant of S6K in response to T3 was not blocked by LY294002, wortmannin, or rapamycin, thus supporting a T3-activated pathway independent of PI3K and mTOR. 40 S ribosomal protein S6, a target of p70(S6K), and 4E-BP1, a target of mTOR, were both phosphorylated within 15-25 min of T3 treatment and could be inhibited by wortmannin and rapamycin. Thus, rapid T3-mediated activation of PI3K by cytosolic TRalpha1 and subsequent activation of the Akt-mTOR-S6K signaling pathway may underlie one of the mechanisms by which thyroid hormone regulates physiological cardiac growth.     

Silent thyroiditis in an eleven-year-old girl, associated with transient increase in serum IgM and thyroid hormone.

An 11-year-old-girl with silent thyroiditis associated with a transient increase in serum IgM and thyroid hormone is described. The levels of serum IgM decreased from 4.38 g/L to 3.35 g/L after 1.5 months at the same time as thyroid hormones returned to normal. An unidentified antecedent infection or exposure to antigen causing the increase in serum IgM might have triggered the occurrence of silent thyroiditis in this patient, although a search for viral antibodies revealed no significant titer changes during the course of the disease.     

Effects of single-dose external gamma irradiation on rat thyroid status as observed during the year

We studied the rat thyroid status depending on the dose of external radiation and the time passed after the exposure. The experiments were carried out on female albino Wistar rats. The doses absorbed amounted to 0.25; 0.5; 1.0; 2.0 and 5.0 Gy. The animals were decapitated after 3, 6, 24 hours and 7, 30, 180 and 365 days following the radiation. The blood serum was assayed for the contents of thyroxin (T4) and triiodothyronine (T3) using a radioimmunological technique. The liver tissue was assayed spectrophotometrically for the activity of thyroid-induced NADP malate dehydrogenase (NADP-MDH). No changes were found in the blood thyroid hormone contents within short periods after the radiation effect. After 6 hours the T4 levels was 1.2-1.3-fold decreased in the blood of rats receiving the radiation doses of 1.0; 2.0; and 5.0 Gy. After a day the T4 concentration was diminished by 1.21-193-fold in all the experimental animals independently of the radiation dose and that of T3--in 2.0 Gy--and 5.0 Gy--irradiated group. After 7 days following the radiation the T4 and T3 contents remained to be decreased by 1.37-1.75 fold and those of NADP-MDH--by 1.3-1.8-fold in all the animal groups. In a month, the low dose-treated animals (0.25, 0.5, 1.0 Gy) showed the level of thyroid hormones reduced to the control values, whereas the 2.0 and 5.0 Gy--treated rats demonstrated this reduction only by 6 months. The decreased concentration of blood thyroid hormones was due not to the activation of their peripheral metabolism, but, probably, to inhibition of their biosynthesis in thyroid cells under conditions of radiation-induced activation of oxidative stress.     

Evidence for a direct effect of thyroid hormones on the hepatic synthesis of estrogen receptors in the rat

The role of thyroid hormones in the regulation of estrogen receptor turnover in the rat liver was studied. Animals subjected to thyroidectomy or hypophysectomy in combination with different hormone substitutions, were used. The receptor level in control animals was 53 fmol/mg cytosol protein. Thyroidectomy for 28 days caused a dramatic reduction to 20 fmol/mg, whereas hypophysectomy for 9 days resulted in an even more substantial reduction to 11 fmol/mg protein. If animals, hypophysectomized for 9 days, were given triiodothyronine (T3) for 9 days the hepatic estrogen receptor concentration was elevated to 22.5 fmol/mg protein. Estradiol given together with T3 did not cause any further increase in the receptor level. We conclude that thyroid hormones affect the hepatic synthesis of estrogen receptors on two levels, via a direct action on the liver and via an indirect modulation of the pituitary hormone synthesis/release.     

Increased thyroidal T4/T3 ratio in nodular and paranodular tissues of nontoxic goiter following suppressive treatment with thyroid hormones

The effect of suppressive treatment with thyroid hormones on thyroidal iodothyronines and T4/T3 ratio in nodular and paranodular tissues was investigated in 12 patients with nontoxic goiter. Results were compared to those from 11 nontreated patients. Continuous thyroid hormone administration produced a significant increase in thyroidal T4 and T4/T3 ratio in nodular tissues while T3 remained unchanged. In paranodular tissues a significant rise of T4/T3 ratio, an insignificant increase in T4 and a decrease in T3 were observed following the administration of thyroid hormones. The results are very similar to those obtained in paranodular tissue of autonomously functioning thyroid nodule, and are probably the consequence of suppressed TSH secretion, as TSH predominantly stimulates the synthesis of T3 and/or thyroidal T4 monodeiodination.     

Lowering of T3 and rise in reverse T3 induced by hyperglucagonemia: altered thyroid hormone metabolism, not altered release of thyroid hormones

Recently we reported that hyperglucagonemia induced by glucagon infusion causes a decline in serum T3 and a rise in reverse T3 in euthyroid healthy volunteers. These changes in T3 and rT3 levels were attributed to altered T4 metabolism in peripheral tissues. However, the contribution of altered release of thyroid hormones by the thyroid gland could not be excluded. Since the release of thyroid hormones is inhibited in primary hypothyroidism and is almost totally suppressed following L-thyroxine replacement therapy, we studied thyroid hormone levels for up to 6 hours after intravenous administration of glucagon in subjects with primary hypothyroidism who were rendered euthyroid by appropriate L-thyroxine replacement therapy for several years. A control study was conducted using normal saline infusion. Plasma glucose rose promptly following glucagon administration demonstrating its physiologic effect. Serum T4, Free T4, and T3 resin uptake were not altered during both studies. Glucagon infusion induced a significant decline in serum T3 (P less than 0.05) and a marked rise in rT3 (P less than 0.05) whereas saline administration caused no alterations in T3 or rT3 levels. Thus the changes in T3 and rT3 were significantly different during glucagon study when compared to saline infusion. (P less than 0.01 for both comparisons). Since, the release of thyroid hormones is suppressed by exogenous LT4 administration in these subjects; we conclude that changes in serum T3 and rT3 observed following glucagon administration reflect altered thyroid hormone metabolism in peripheral tissues and not altered release by the thyroid gland.     

Alterations in thyroid hormone physiology induced by temperature and feeding in newly hatched chickens

In the chicken the transition of a poikilotherm to a homeotherm reaction upon cold exposure takes place in the perinatal period between pipping and hatching. However, newly hatched chicks cannot maintain their body temperature within narrow limits after cold exposure. The fact that relatively little attention was payed on the role of thyroid hormones in the thermoregulatory reaction to cold of young chicks was probably due to the hypothetically long latention time that was thought to be necessary to bring about changes in secretory activity by cold stimulation. However, more recently, rapid changes (within hours) of thyroid hormone concentrations upon cold exposure were described in the chickens and the quail. In this study, changes in circulating T3 and T4 concentrations upon cold exposure of young chicks during the first two weeks were followed, that means during the period wherein NST (non-shivering thermogenesis), if it exists at all, should be progressively replaced by ST (shivering thermogenesis). Because of the importance of feeding condition on thyroid hormone levels, the experiments were carried out with and without a preceeding fasting period. In all experiments a short-term cold exposure of young chickens (1-11 days) fed ad lib decreased T3 but increased T4 levels while a reversed picture was found after short cold exposure of the fasted animals. However, after prolonged cold stimulus (15 degrees C) of young chickens fed ad lib, plasma T3 was also significantly elevated over that of controls whereas T4 levels returned to normal values. A prolonged warm treatment (37 degrees C) of young chickens fed ad lib resulted in significantly lower T3 and higher T4 concentrations. After a prolonged cold treatment no differences in T4 or T3 response upon TRH were found whereas the warm treatment abolished these responses upon TRH. However, a cold treatment at the stage of incubation during which the hypothalamo-hypophyseal control of thyroid function is established (dag 10-14) enhanced the T4 response to TRH with a long lasting effect extending to the posthatch period. Since T3 is thought to be the active form of thyroid hormones with regard to thermopoiesis we have studied more specifically the effect of blocking peripheral conversion of T4 on thermoregulatory abilities in young chicks and the influence of temperature treatment on monodeiodination capacity. The lower rectal temperatures following the interference with the peripheral monodeiodination of T4, the effect being more pronounced at the lower ambient temperature, are indicative for a preponderant role of T3 on thermogenesis.(ABSTRACT TRUNCATED AT 400 WORDS)     

Rapid and transient reduction in circulating thyroid hormones following systemic antigen priming: implications for functional collaboration between dendritic cells and thyroid.

The thyroid hormones T(3) (tri-iodothyronine) and T(4) (thyroxine) are disseminated throughout the body via the circulation and are maintained across a range of physiological concentrations under the control of thyroid-stimulating hormone (TSH). T(3) (and T(4) after conversion to T(3)) influences many biological activities, including gene expression and protein synthesis, though little is known about the nature of pituitary-thyroid immune interactions. In the present study we show that serum T(3) and T(4) levels are sharply but transiently reduced during the first 24 h of systemic antigen exposure and that this is followed by suppressed levels of free T(4), after which there is rapid recovery to normal levels. Splenic dendritic cells, depending upon the stage of maturation/activation, were found to be a rich source of TSH, and CD11c(+) cells with dendritic cell morphology were present in the thyroid 1-3 days after antigen exposure. Moreover, antigen priming of hypophysectomized mice that are unable to make pituitary-derived TSH resulted in significant increases in circulating T(4), implying that compensation in the drop in thyroid hormones can be regulated from extrapituitary sources. These findings thus identify a novel set of immune-endocrine interactions that transpire during the early phase of antigen exposure, and they suggest that under appropriate conditions the immune system directly participates in the process of maintaining physiological homeostasis by contributing to the regulatory control of thyroid hormone activity.