calcimycin and Thyroid-Neoplasms

The oxidative processes (oxygen consumption, superoxoid anion generation, arachidonic acid cascade) of human polymorphonuclear granulocytes (PMNs) obtained from patients suffering from thyroid disorders of autoimmune origin (Graves' disease and Hashimoto's thyroiditis), and non autoimmune origin (toxic adenoma) were investigated. All Graves' and toxic adenoma patients were hyperthyroid. Hashimoto's thyroiditis patients were euthyroid. Healthy age and sex matched volunteers served as controls. The results are as follows: 1) In PMNs from both hyperthyroid groups (Graves' disease and toxic adenoma), independently from the autoimmune origin of the disease, a significantly increased Antimycin A sensitive mitochondrial oxygen consumption and a slightly increased superoxide anion generation were detected. 2) In both autoimmune thyroid disease groups (Graves' disease and Hashimoto's thyroiditis)--depending on the functional state of the thyroid gland--a significantly altered intracellular killing activity was measured. 3) An increased arachidonic acid cascade--triggered by opsonized zymozan (OZ)--was detected in both autoimmune thyroid diseases. The increased arachidonic acid cascade was sensitive to phospholipase A2 inhibiting Mepacrin treatment. 4) The PMNs from both autoimmune thyroid diseases produced large amount of leukotriens (LTs)--LTC4 and LTB4--after stimulation through their Fc receptors but the synthesis of prostagalandins (PGs) has not changed. There are no data indicating local, specific effects of circulating leukotriens in the thyroid gland itself, but based on authors' data, their general, regulating role on both the endocrine-- as well as on the immune system--seems to be plausible.

Topics: Adenoma; Adult; Arachidonic Acids; Calcimycin; Candida albicans; Dinoprostone; Female; Graves Disease; Humans; In Vitro Techniques; Leukotriene B4; Leukotriene C4; Middle Aged; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Oxygen Consumption; Phagocytosis; Reference Values; Respiratory Burst; Superoxides; Thyroid Neoplasms; Thyroiditis, Autoimmune; Thyroxine; Zymosan

The effects of TSH and the activation of the cyclic AMP (cAMP) and Ca(2+)-phosphatidylinositol (Ca(2+)-PI) cascades on the activity and expression of the selenoenzyme thyroidal type-I iodothyronine deiodinase (ID-I) have been studied using human thyrocytes grown in primary culture. Stimulation of ID-I activity and expression was obtained with TSH and an analogue of cAMP, 8-bromo-cAMP. In the presence or absence of TSH, the addition of the phorbol ester, phorbol 12-myristate 13-acetate (PMA) together with the calcium ionophore A23187, caused a decrease in ID-I activity; a decrease in ID-I expression was also observed as assessed by cell labelling with [75Se]selenite. PMA alone had no effect on ID-I activity in the presence or absence of TSH. A23187 alone produced a small but significant reduction in ID-I activity, but only in TSH-stimulated cells. These data provide evidence that the expression of thyroidal ID-I is negatively regulated by the Ca(2+)-PI cascade, and positively regulated by the cAMP cascade.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Calcimycin; Calcium; Carcinoma; Cells, Cultured; Cyclic AMP; Dimethyl Sulfoxide; Enzyme Induction; Graves Disease; Humans; Iodide Peroxidase; Microsomes, Liver; Phosphatidylinositols; Proteins; Selenoproteins; Signal Transduction; Sodium Selenite; Tetradecanoylphorbol Acetate; Thyroid Gland; Thyroid Neoplasms; Thyroid Nodule; Thyrotropin

Three intracellular signal transduction pathways have been found to be utilized by gamma-interferon (IFN-gamma) in the induction of HLA-DR in several cell types, mainly monocytes/macrophages and B-cells: the protein kinase A (PKA); Ca(2+)-calmodulin; and protein kinase C (PKC) pathways. In this study, we investigated the role of these pathways in IFN-gamma-induced HLA-DR expression in normal and neoplastic human thyroid cells. The PKA pathway seemed to inhibit both neoplastic and normal IFN-gamma-induced HLA-DR expression; addition of thyroid-stimulating hormone to normal thyroid cells, as well as 8-bromo cyclic AMP and forskolin to normal and neoplastic cells, reduced the amount of IFN-gamma-induced HLA-DR. Moreover, H-8, a PKA inhibitor, enhanced such IFN-gamma-induced HLA-DR expression. The calcium-calmodulin pathway does not seem to play a role in IFN-gamma-induced HLA-DR expression in normal and neoplastic thyrocytes, since the Ca-ionophore A23187, EGTA, and the calmodulin antagonist, W-7, neither induced HLA-DR nor showed any effect on HLA-DR expression induced by IFN-gamma. Alone, phorbol 12-myristate 13-acetate, a PKC activator, did not induce HLA-DR on thyroid cells. However, its addition to neoplastic cells together with IFN-gamma caused a synergistic elevation of the expressed HLA-DR, whereas it significantly inhibited IFN-gamma-induced HLA-DR in normal thyrocytes. TPA had to be added before or together with IFN-gamma for optimal function. If added more than 6 h after IFN-gamma, TPA was not effective. An inactive TPA analogue did not affect HLA-DR induction, while an active analogue mimicked TPA. Staurosporine, a PKC inhibitor, reduced the TPA enhancing effect in neoplastic thyrocytes and cancelled TPA inhibition in normal cells. Moreover, when added to IFN-gamma without TPA in normal thyroid cells, staurosporine increased 3- to 4-fold the amount of HLA-DR. Thus, in normal thyroid cells the PKC pathway is activated by IFN-gamma and inhibits HLA-DR expression. In neoplastic thyrocytes, although IFN-gamma does not induce HLA-DR via PKC, this pathway augments HLA-DR expression.

Topics: Alkaloids; Calcimycin; Carcinoma; Cells, Cultured; Dose-Response Relationship, Drug; Drug Administration Schedule; Goiter; HLA-DR Antigens; Humans; Interferon-gamma; Isoquinolines; Signal Transduction; Staurosporine; Tetradecanoylphorbol Acetate; Thyroid Neoplasms; Tumor Cells, Cultured

Examination was made of the effects of gastrin-releasing peptide (GRP) on human medullary thyroid carcinoma cells (TT cells). GRP stimulated calcitonin(CT) release in a concentration-dependent manner at 0.1-1000 nmol/l. On adding forskolin along with GRP, CT release was greater than by GRP alone. The stimulatory effect of A23187 was not additive. Intracellular free calcium concentration ([Ca2+]i) was measured for individual TT cells loaded with fura-2. The addition of GRP caused a rapid and transient rise in [Ca2+]i in a concentration-dependent manner followed by a sustained increase in [Ca2+]i. In the medium without Ca2+, this sustained increase did not occur and the concentration of CT release from TT cells by GRP was reduced by approximately a half. GRP would thus appear to be importantly involved in the regulation of thyroid C cell function through modulation of [Ca2+]i.

Topics: Calcimycin; Calcitonin; Calcium; Cell Line; Colforsin; Cytoplasm; Dose-Response Relationship, Drug; Egtazic Acid; Fura-2; Gastrin-Releasing Peptide; Gastrointestinal Hormones; Humans; Kinetics; Peptides; Thyroid Neoplasms; Virulence Factors, Bordetella

Synthesis of leukotriene B4 (LTB4) upon stimulation of peripheral blood samples with the calcium ionophore A 23187 was studied in patients with primary hyperparathyroidism who underwent parathyroidectomy. Preoperatively, an increased LTB4 concentration of 1.76 +/- 0.19 ng/ml plasma was found, vs. 0.95 +/- 0.28 ng/ml in healthy individuals. On the fourth day after operation, the LTB4 concentration was almost normalized, reaching 1.25 +/- 0.23 ng/ml plasma. At the same time, mean serum calcium levels were reduced from 6.1 +/- 0.6 meq/liter before operation to 4.53 +/- 0.28 meq/liter after operation. In a control group, euthyroid patients with thyroid adenomas who underwent adenomectomy had normal LTB4 levels before operation (0.84 +/- 0.11 ng/ml) and did not show significant changes in LTB4-synthesizing capacity. The results indicate that synthesis of LTB4 in vivo may depend in part on factors related to serum calcium concentration or calcium metabolism.

Topics: Adenoma; Calcimycin; Calcium; Humans; Hyperparathyroidism; Leukotriene B4; Neutrophils; Parathyroid Glands; Thyroid Neoplasms

We have investigated the regulation of the human throid gland based on controls discovered in the dog thyroid gland. TSH and thyroid-stimulating immunoglobulin enhanced cAMP accumulation, which supports the validity of the Sutherland model for the action of TSH on the human thyroid. Iodide inhibited TSH- and thyroid-stimulating immunoglobulin-activated cAMP accumulation and this effect was reduced by methimazole, showing that, in this tissue, iodide, through an oxidized derivative, depresses the TSH-cAMP system. Contrary to the hypothesis of a short feedback loop of thyroid hormone, no thyroid effect of T3 or T4 was found. Adrenergic agents (norepinephrine and isoproterenol) enhanced cAMP accumulation; this effect was inhibited by dl-propranolol but not by d-propranolol or phentolamine. This suggests a positive control of the thyroid cAMP system by beta-adrenergic receptors. Histamine also increased cAMP accumulation. However, the role of these controls is unknown. Acetylcholine, by a muscarinic type effect, enhanced cGMP accumulation and prostaglandin E2 and prostaglandin F2 alpha release. These effects were mimicked by ionophore A23187 and abolished in a calcium-deprived medium, which suggests that they are secondary to a raised Ca++ influx. The results are summarized in a general working model of human thyroid regulation. These biochemical controls have been compared in normal tissue and autonomous nodules. No evidence of increased sensitivity to TSH of the nodular tissue was found. On the other hand, this tissue was less sensitive to acetylcholine (cGMP accumulation) and more sensitive to norepinephrine (cAMP accumulation).

Topics: 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; Acetylcholine; Adenoma; Adult; Atropine; Calcimycin; Carbachol; Cholera Toxin; Cyclic AMP; Cyclic GMP; Female; Fluorides; Humans; Middle Aged; Physostigmine; Prostaglandins; Prostaglandins E; Thyroid Gland; Thyroid Neoplasms; Thyrotropin