calcimycin and Graves-Disease

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

To elucidate the pathogenesis of thyroid gland hypervascularity in patients with Graves' disease, we studied the expression of mRNAs for vascular endothelial growth factor (VEGF) and its receptor, Flt family, using human thyroid follicles in vitro and thiouracil-fed rats in vivo. Human thyroid follicles, cultured in the absence of endothelial cells, secreted de novo-synthesized thyroid hormone in response to thyroid-stimulating hormone (TSH) and Graves' IgG. The thyroid follicles produced VEGF mRNA but not flt-1 mRNA. The expression of VEGF mRNA was enhanced by insulin, tumor-promoting phorbol ester, calcium ionophore, dibutyryl cAMP, TSH, and Graves' IgG. When rats were fed thiouracil for 4 wk, their serum levels of TSH were increased at day 3. VEGF mRNA was also increased on day 3, accompanied by an increase in flt family (flt-1 and KDR/ flk-1) mRNA expression. These in vitro and in vivo findings suggest that VEGF is produced by thyroid follicles in response to stimulators of TSH receptors, via the protein kinase A and C pathways. VEGF, a secretable angiogenesis factor, subsequently stimulates Flt receptors on endothelial cells in a paracrine manner, leading to their proliferation and producing hypervascularity of the thyroid gland, as seen in patients with Graves' disease.

Topics: Animals; Bucladesine; Calcimycin; Cell Division; Cells, Cultured; Culture Media, Conditioned; DNA Probes; Dose-Response Relationship, Drug; Endothelial Growth Factors; Gene Expression; Graves Disease; Humans; Immunoglobulin G; Insulin; Kinetics; Lymphokines; Proto-Oncogene Proteins; Rats; Receptor Protein-Tyrosine Kinases; Receptors, Growth Factor; RNA, Messenger; Tetradecanoylphorbol Acetate; Thiouracil; Thyroid Gland; Thyrotropin; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors