Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.11.1.8 (thyroid peroxidase)
3,116 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have further characterized the biological activities, mechanism of action, and target cell populations of recombinant human and murine thrombopoietin (rhTPO and rmTPO) in in vitro human and murine model systems. Alone, hTPO or mTPO stimulated the maturation of immature murine megakaryoblasts as measured in a single cell assay. The combination of hTPO or mTPO and interleukin-6 (IL-6) resulted in a further increase in megakaryocyte differentiation in this system. Murine TPO stimulated mouse megakaryocyte progenitor development. Human megakaryocyte progenitor development was potentiated by hTPO alone and further augmented in the presence of the early-acting cytokines (IL-3) or kit ligand/stem cell factor (KL/SCF). To further define the mechanism of action of TPO, neutralization studies were performed with antisera to IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-1 beta, and IL-11. No diminution in TPO activity was observed in the presence of these antisera. Moreover, because adhesive interactions are known to modulate hematopoiesis, we studied whether hTPO might alter such interactions between human bone marrow (BM) megakaryocytes and human BM stromal fibroblasts. No changes were observed in either megakaryocyte expression of the surface molecules lymphocyte function-associated antigen-1, very late activation antigen-4, or intercellular adhesion molecule-1 or the adhesion of megakaryocytes to stromal fibroblasts after treatment with the growth factor. Furthermore, no induction of secretion of the cytokines IL-1 alpha, IL-1 beta, GM-CSF, IL-6, granulocyte-CSF, tumor necrosis factor-alpha, transforming growth factor-beta 1, or transforming growth factor-beta 2 by primary human BM megakaryocytes was noted after treatment of the cells with hTPO. To address whether TPO affects very primitive hematopoietic progenitors, we studied the residual cells from the BMs of mice treated with high doses of 5-fluorouracil. Although no effect of mTPO alone was noted on the viability or replication of such primitive murine progenitor populations, the triple combination of IL-3 + KL/SCF + TPO stimulated growth of megakaryocyte progenitors. These results indicate that TPO is a highly lineage-specific growth factor whose primary biological effects are likely to be direct modulation of the growth and maturation of committed megakaryocyte precursors and immature megakaryoblasts.
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PMID:Modulation of megakaryocytopoiesis by thrombopoietin: the c-Mpl ligand. 763 39

Thrombopoietin (Tpo) is a cytokine that specifically regulates megakaryocyte maturation and platelet production. Little is known about the molecular and cellular mechanism of the Tpo-induced megakaryocyte maturation process including polyploidization and platelet release. To study Tpo-induced megakaryocyte differentiation, a mouse cell line FD-TPO, which responds and grows with Tpo, was established from a interleukin-3-dependent hematopoietic progenitor cell line FDC-P2. The FD-TPO cells, expressing endogenous Tpo receptor, grew with Tpo in a dose-dependent manner. Further, Tpo stimulation dramatically induced expression of megakaryocyte/erythroid-specific transcription factors GATA-1 and NF-E2 in FD-TPO cells. Flow cytometry analysis demonstrated that expression of platelet-specific cell surface antigens including CD61 (GPIIIa) dramatically increased in Tpo-stimulated FD-TPO cells and that expression of myeloid-specific antigens, Gr-1 and Mac-1, decreased. Therefore, we concluded that the binding of Tpo to FD-TPO cells induces not only cell growth but also differentiation into mature megakaryocyte-like cells, and thus this cell line was found to be useful for the study of Tpo receptor-mediated growth and differentiation signals.
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PMID:Thrombopoietin induces megakaryocyte differentiation in hematopoietic progenitor FDC-P2 cells. 764 75

The aim of this study was to assess whether the presentation and progression of autoimmune postpartum thyroiditis (PPT) was related to the degree of thyroid peroxidase autoantibody (TPO-ab)-mediated activation of the complement cascade. One hundred and forty-eight thyroid autoantibody-positive women have been followed during their postpartum year. Seventy-five women remained euthyroid during this time whilst the remaining 73 showed one or more episodes of thyroid dysfunction. Fourteen women showed hyperthyroid PPT, 23 showed a biphasic PPT and the remaining 36 showed hypothyroid PPT. Hyperthyroid PPT was always transient but 29 of the 59 women with hypothyroidism remained hypothyroid or still required thyroxine replacement therapy at the conclusion of the study. Thyroid autoantibodies were measured by enzyme-linked immunosorbent assay (ELISA), free triiodothyronine and free thyroxine by the Amerlex M methods and thyrotrophin by the Amerlite TSH (monoclonal) assay. Complement component C3b, immobilized as a result of classical complement pathway activation in the presence of TPO/TPO-ab complexes in vitro, was measured by ELISA. Bioactive TPO-ab were calculated as the product of the C3 index and TPO-ab level. Basal levels of complement C3 activation were seen in the euthyroid TPO-ab-positive women (C3 index 0.06 at delivery rising to 0.36 at 12 months postpartum; bioactive TPO-ab activity 0.4 kIU/l at delivery rising to 10.4 kIU/l at 12 months' postpartum (N = 75). These parameters were elevated progressively as the severity of the clinical syndrome increased. In 14 hyperthyroid PPT women the C3 index was 0.47 at 8 months' postpartum (bioactive TPO-ab activity = 20 kIU/I; p vs euthyroid group, NS).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of complement in the pathogenesis of postpartum thyroiditis: relationship between complement activation and disease presentation and progression. 765 46

The upper limit of normal TSH levels, determined with a second generation kit (RIA-Gnost TSH, Behring) was set at 2.8 microU/ml. These TSH levels define pituitary reactivity in euthyroid subjects. The upper limit for TSH 20 minutes after injection of TRH was set at 23 microU/ml. The diagnosis of infraclinal hypothyroidism should be made in patients with a normal hormone level, normal baseline TSH and a positive response to TRH defined as a TSH above the upper limit 20 minutes after injection. A large percentage of these patients were positive for anti-TPO antibodies, emphasizing the risk of developing patent hypothyroidism. Clinicians should be aware of the need to lower the upper limit for baseline TSH, often set a 4 or even 6 microU/ml. A level of 2.8 to 4 microU/ml is recommended as the upper limit. Within this interval, the TRH test should always be performed since 50% of the TSH values obtained under in such patients are abnormal.
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PMID:[Contribution of TRH test and anti-TPO antibody assay in the screening of infraclinical hypothyroidism]. 767 8

This chapter has outlined the complex process required for thyroid growth and function. Both events are regulated by TSHR via a multiplicity of signals, with the aid of and requirement for a multiplicity of hormones that regulate the TSHR via receptor cross-talk: insulin, IGF-I, adrenergic receptors, and purinergic receptors. Cross-talk appears to regulate G-protein interactions or activities induced by TSH as well as TSHR gene expression. The TSHR structure and its mechanism of signal transduction is being rapidly unraveled in several laboratories, since the recent cloning of the receptor. In addition, the epitopes for autoantibodies against the receptor that can subvert the normal regulated synthesis and secretion of thyroid hormones, causing hyper- or hypofunction, have been defined. Studies of regulation of the TSHR minimal promotor have uncovered a better understanding of the mechanisms by which TSH regulates both growth and function of the thyroid cell. A key novel component of this phenomenon involves TSH AMP positive and negative regulation of the TSHR. Negative transcriptional regulation is a common feature of MHC class I genes in the thyroid. Subversion of negative regulation or too little negative regulation is suggested to result in autoimmune disease. Methimazole and iodide at autoregulatory levels may be important in reversing this process and returning thyroid function to normal. Their action appears to involve factors that react with the IREs on both the TSHR and the TG promoter. Too much negative regulation, as in the case of ras transformation, results in abnormal growth without function. TTF-1 is implicated as a critical autoregulatory component in both positive and negative regulation of the TSHR and appears to be the link between TSH, the TSHR, TSHR-mediated signals, TG and TPO biosynthesis, and thyroid hormone formation. Differentially regulated expression of the TSHR and TG by cAMP and insulin depend on differences in the specificity of the TTF-1 site, that is, the lack of Pax-8 interactions with the TSHR, and the IRE sites. Single-strand binding proteins will become important in determining how TSHR transcription is controlled mechanistically.
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PMID:The thyrotropin receptor. 770 2

A. A dysfunction of the thyroid gland can be safely excluded when the local finding of the thyroid gland, perhaps including an ultrasound, is normal and the TSH-levels are unchanged (between 0.4 and 4.0 microE/ml). B. A hyperthyreosis can be proven in 98% when TSH is suppressed (possibly a negative TSH-test) and the T3 levels and the FT3 levels, respectively, are elevated. Following examinations are necessary for the further diagnostics: When a Base-dow hyperthyreosis is suspected, T4, TR and TPO antibodies should be measured and an ultrasound obtained. When a focal or disseminated autonomy is suspected, a scintigraphy and suppression scintigraphy, respectively as well as an ultrasound should be undertaken. C. A hypothyreosis can be proven in 98% when TSH is elevated (possibly an overshooting TSH test), and the T4 levels are low. For further diagnostics, ultrasound and maybe scintigraphy should be undertaken in case of a congenital hypothyreosis. In case of an acquired hypothyreosis, TR and TPO antibodies should be measured, an ultrasound obtained, and a cytology might be taken to exclude a thyreoiditis De Quervain or a Hashimoto thyreoiditis.
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PMID:[Rational diagnosis of disorders of thyroid function]. 770 40

We evaluated the prevalence of antithyroid peroxidase antibodies (anti-TP0 Ab) in 402 patients with thyroid disease and 30 healthy controls by a commercial radioimmunoassay (RIA) and compared the results with the passive hemagglutination (HA) method. The patients in the study had autoimmune thyroid disorders (AITD) such as Graves' disease and Hashimoto's disease or had nonautoimmune thyroid diseases (NAITD) such as thyroid cancer, congenital goiter, endemic goiter, and nodular goiter. Subjects were recruited from a population with a mild iodine deficiency (Sao Paulo, Brazil). The effect of specific therapy (for either thyrotoxicosis or chronic thyroiditis) on the circulating anti-TPO levels was also investigated. Positive anti-TPO Ab was detected in 89.9% of the patients with AITD as compared with a prevalence of positive tests of only 4.8% in patients with NAITD. Positive microsomal antibody (M Ab) was found in 68.4% of the patients with AITD and in 6.4% of the patients with NAITD. A positive and significant correlation was obtained between M Ab and anti-TPO Ab. A positive anti-TPO test with negative anti-M was found in 14.1% of the patients with AITD but in only 4.3% of the patients with NAITD and normal controls. These results suggest that anti-TPO Ab by RIA is more sensitive and specific than M Ab by HA. In patients with AITD, anti-TPO Ab levels usually decreased after treatment, suggesting that this parameter could be used in the follow-up of these thyroid disorders.
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PMID:Prevalence of anti-thyroid peroxidase antibodies in autoimmune and nonautoimmune thyroid disorders in a relatively low-iodine environment. 774 31

The measurement of serum TPO Ab and Tg Ab by a new direct sensitive RIA in this study are quantitative and provided a convenient system. When compared to the commonly used PH technique for TM Ab and Tg Ab, this RIA determination appears to be more sensitive than by PH, since it enabled detection of TPO Ab and/or Tg Ab in sera that were negative by PH. Thus, this RIA determination should be more widely used in a clinical laboratory.
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PMID:Evaluation of a new direct radioimmunoassay for serum thyroid peroxidase and thyroglobulin antibodies. 787 50

Segregation analysis has suggested that the inheritance of thyroid autoantibodies (to thyroglobulin and to thyroid peroxidase) is a dominant Mendelian trait. In this study we describe an attempt to find the chromosomal location(s) of gene(s) responsible for thyroid autoantibody production. We have examined a number of restriction length polymorphisms (RFLPs) and highly polymorphic markers (mini- and microsatellite) for genetic linkage with thyroid autoantibodies using a panel of 16 families with autoimmune thyroid disease. None of the markers used in this study gave evidence of linkage, however minisatellite markers (MS1, MS31, MS32, MS43a, M851, G3) for TPO antibody, minisatellite markers (MS1, MS32, MS43a, MS51, G3) for Tg antibody, and all microsatellite markers used, provided evidence for exclusion of genetic linkage.
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PMID:Genetic linkage analysis of thyroid autoantibodies. 790 61

In autoimmune thyroid disease there are various autoantibodies (Ab) to thyroid cell components. Among the best characterized are those to thyroid peroxidase (TPOAb) and to the thyrotropin receptor (TRAb). While TPOAb were successfully used to visualize TPO in human thyroid cells (HTC) and a rat thyroid cell line (FRTL5) by indirect immunofluorescence (IFL), similar attempts with TRAb and thyrotropin receptor (TSHR) failed. This could have been due to either relatively low serum levels of TRAb and/or low number of TSHR on thyroid cells. To test these hypotheses, we estimated the number of TSH binding sites on HTC, FRTL5 and Chinese hamster ovary (CHO) cells, transfected with cloned human TSHR (JP-26 cells), and for IFL staining employed 3 sera with the highest potency TRAb in our possession. A clear granular surface staining was detected on all 3 cell types with two sera; with the third, the least potent, no staining was seen. The density of staining paralleled the estimated number of TSHR per cell, i.e., JP-26 > FRTL5 > HTC. TSHR was also visualized on transiently transfected cells (COS-7-TSHR), facilitating quantitation of transfection. Our results suggest that the limiting factor in direct visualization of the TSHR is the TRAb concentration.
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PMID:Visualization of the thyrotropin receptor on the cell surface by potent autoantibodies. 790 19


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