Growth factors in thyroid cells.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
R Gärtner
Publications and source records attributed to R Gärtner.
[Wanting a child in Hashimoto thyroiditis with hypothyreosis].
Explore the source record for details and available documents.
Adult↗
Influence of knowledge on iodine content in foodstuffs and prophylactic usage of iodized salt on urinary iodine excretion and thyroid volume of adults in southern Germany.
Thyroid volume, urinary iodine excretion as well as personal nutritional knowledge and individual iodine prophylaxis were determined during a health education program on iodine deficiency and prophylaxis in 1992. Participants were 472 male and 568 female (mean age 27.7 years) students and employees of five universities in the southern part of Germany. The study aimed to clarify the relationship between personal knowledge on iodine, individual iodine prophylaxis and parameters of iodine deficiency (thyroid volume, iodine excretion) in a well known iodine deficient area. Mean thyroid volume (mean +/- SD) was 19.7 +/- 8.3 ml in males and 15.8 +/- 7.1 ml in females. 25.5% of females and 19.9% of males showed thyroid volume above the upper normal values. Total mean urinary iodine excretion was 70.7 +/- 42 micrograms I/g creatinine reflecting WHO-grade-I iodine deficiency. 80.8% of total subjects used iodized salt and 43.2% stated to consume salt-water fish to meet their iodine requirement. The female non-users had significantly lower iodine excretion (no iodized salt, no salt-water fish: 61.4 +/- 31.3 vs. +iodized salt, +salt-water fish: 83.9 +/- 47.6 micrograms I/g creatinine; p < 0.05), however, thyroid volume was identical in these groups. The area of residence over the last 10 years did not significantly influence the thyroid volume. The goiter incidence increased with age. Although our study population was highly educated (81.8% students) and the subjects were provided with educational brochures immediately prior to the study, knowledge about iodine content of food was poor. We conclude that despite a high degree of voluntary iodine prophylaxis and educational programs the iodine intake is insufficient. The use of iodized salt in households, cafeterias, and also in food manufacturing must be increased for sufficient iodine prophylaxis.
Adult↗
Comment on: goiter benign disease.
Explore the source record for details and available documents.
Animals↗
Role of basic fibroblast growth factor in the pathogenesis of nodular goiter.
Thyroid epithelial cells are known to produce several growth factors and cytokines which influence thyroid cell growth and function in an autocrine and/or paracrine manner. It is already known that insulin-like growth factor I (IGF I) is overexpressed in toxic adenomas whereas epidermal growth factor (EGF) is found predominantly in thyroid neoplasia. We now investigated the expression of bFGF by immunohistochemistry in thyroid tissue of patients with toxic adenoma (n = 27), cold nodules (n = 27) and for comparison in Graves' disease (n = 5). In addition bcl-2-oncoprotein expression in these tissues were also detected by immunohistochemistry. Most of bFGF immunostaining was found in the connective tissue of all thyroid tissues with a predominance in adenomas and in Graves' diseases. The collagen surrounding the thyroid follicles close to their basal membrane were homogeneously and intensively stained. All the cytoplasm of fibroblast in the connective tissue were strongly positive. Within the cytoplasm of only 2-10% thyroid epithelial cells bFGF immunostaining was found without any difference between toxic adenomas or cold nodules. In the tissue of patients with Graves' disease, less than 2% of thyrocytes were stained. All thyroid epithelial cell showed clearly an immunostaining for bcl-2-oncoprotein in nodular goiter as well as Graves' disease.
Adenoma↗
Stimulation of thyroid cell proliferation by epidermal growth factor is different from cell growth induced by thyrotropin or insulin-like growth factor I.
Isolated intact porcine thyroid follicles free of contaminating single cells were embedded in "Matrigel", which is a gel-forming basement membrane preparation containing mainly collagen type IV, laminin, heparan sulfate proteoglycans and entactin. Follicles were treated with different growth factors: thyrotropin (TSH), insulin-like growth factor I (IGF-I), epidermal growth factor (EGF) or transforming growth factor beta. Cell proliferation was quantified by counting cell numbers. Morphological studies were done by photodocumentation and analysis of histology by light and electron microscopy. The thyrocytes had the physiological polarity with follicular cell arrangement, microvilli at the apical membrane, desmosomes and tight junctions. The lumen contained colloid. Iodide organification (10.2 +/- 2.1 vs 26.1 +/- 5.8 pmol/10(6) cells; TSH 0.1 mU/ml) and release of thyroid hormones (thyroxine, 1754 +/- 207 vs 2890 +/- 460 pg/10(6) cells; triiodothyronine, 164 +/- 22 vs 412 +/- 106 pg/10(6) cells; TSH, 1mU/ml) were significantly stimulated by TSH. There was no basal growth rate in serum-free medium but proliferation was slightly stimulated with TSH (1 mU/ml; 149 +/- 19%) and in the same order of magnitude with IGF-I (10 ng/ml; 159 +/- 23%) but without follicle neoformation. In contrast, BGF (1.0-5.0 ng/ml) induced thyrocyte proliferation dose dependently three- to sixfold. With BGF up to 2 ng/ml, buds of new follicles formed surrounding pre-existing follicles. With BGF higher than 3 ng/ml, typical papillary structures developed. Transforming growth factor beta inhibited this dedifferentiated growth. A migration of single cells into the gel was never observed. Thus, three-dimensional culture of isolated thyroid follicles in "Matrigel" provides a tool for investigating the regulation of follicular growth and neoformation close to the in vivo situation.
Animals↗
Evidence that iodolactones are the mediators of growth inhibition by iodine on the thyroid.
Different iodolipids have been identified within the last decades in thyroid cells exposed to iodine in vitro as well as in vivo. Iodolipids have been supposed to be involved in thyroid autoregulation, but no specific compounds could be found. A new approach was stimulated by the finding that rat thyroid lobes were able to iodinate arachidonic acid and docosahexaenoic acids in vitro. Meanwhile 6-iodo-5 hydroxy-eicosatrienoic acid (delta-iodolactone) has been identified in human thyroid tissue, but only after treating the patients with high doses of iodine before thyroidectomy, whereas in untreated endemic goiter this delta-iodolactone could not be found. In rats treated with iodolactones, methimazole induced goiter formation could be prevented. In human and porcine thyroid cells in vitro, delta-iodolactone inhibited epidermal growth factor (EGF) induced proliferation in 50-fold lower concentrations than iodide itself. Furthermore it could be demonstrated that only the IP3-, but not the cAMP generation in porcine thyroid cells could be inhibited by this compound. Also a structure specifity for delta-iodolactones for the biological activity could be shown. We will summarize and discuss these important new findings on the role of iodolactones on thyroid growth.
Animals↗
Insulin-like growth factor I messenger ribonucleic acid expression in porcine thyroid follicles is regulated by thyrotropin and iodine.
Insulin-like growth factor I (IGF-I) has been shown to be released from thyrocytes in vitro. We investigated IGF-I mRNA expression during treatment with thyrotropin (TSH), forskolin and potassium iodide (KI) in intact porcine thyroid follicles ex vivo. Porcine thyroid follicles were prepared by collagenase digestion and cultured in the presence of TSH, forskolin or KI. After different incubation times, mRNA was isolated and examined by Northern hybridization with a porcine IGF-I cDNA probe of 405 bp in length. In untreated follicles no IGF-I mRNA was found, whereas in follicles stimulated with TSH an IGF-I mRNA of 7.0 kb was detected after 24 h, which persisted for another 24 h. Forskolin treatment mimicked the TSH effect, indicating that IGF-I mRNA expression may be stimulated by the adenylate cyclase pathway. Preincubation of the porcine follicles with KI decreased dose dependently the TSH-induced IGF-I mRNA expression, with complete inhibition at 10 mumol/l KI. These results suggest that TSH acts via the cAMP pathway to enhance IGF-I mRNA expression, which then may lead to an autocrine IGF-I stimulation. The IGF-I mRNA expression is under negative control of iodide.
Adenylyl Cyclases↗
delta-Iodolactones decrease epidermal growth factor-induced proliferation and inositol-1,4,5-trisphosphate generation in porcine thyroid follicles--a possible mechanism of growth inhibition by iodide.
delta-Iodolactone (6-iodo-8,11,14-eicosatrienoic delta-lactone, delta-IL), an iodinated derivative of arachidonic acid, has been shown to be synthesized in thyroid tissue and to inhibit thyroid cell proliferation. It is discussed as a potential mediator of the autoregulatory pathway of iodide in cyclic adenosine-3',5'-monophosphate (cAMP)- and thyrotropin (TSH)-independent growth. We therefore further localized the action of iodide and of delta-IL in isolated porcine thyroid follicles. Epidermal growth factor (EGF) and 12-O-tetradecanoylphorbol-13-acetate (TPA) dose dependently stimulated thyroid cell proliferation, which could be inhibited by staurosporin (0.1-10 nmol/l). Iodide (2.5-40 mumol/l) as well as delta-IL (0.5-2 mumol/l) also dose dependently inhibited EGF- and TPA-induced proliferation. As the calcium ionophor A23187 (100 pmol/l) completely abolished the inhibitory effects of iodide and of delta-IL, this may indicate a mechanism of delta-IL at or proximal to the calcium-dependent activation of protein kinase C. The growth inhibitory effect was restricted to delta-iodolactones when delta-IL was compared to 6-iodo-8,11,14,17-eicosatetraenoic delta-lactone and 5-iodo-7,10,13,16,19-docosapentaenoic gamma-lactone. It could not be prevented with propylthiouracil and therefore deiodination and a different iodide action is unlikely. Inositol-1,4,5-trisphosphate (IP3) and cAMP were measured in extracts from isolated porcine thyroid follicles stimulated with EGF (10 ng/ml) or TSH (1.0 U/l) revealing comparable kinetics in IP3 generation, while cAMP formation was only stimulated by TSH. delta-Iodolactone (2 mumol/l) only decreased EGF-induced IP3 formation, whereas TSH-induced IP3 and cAMP formation was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
[Etiopathogenesis and therapy of iodine deficiency goiter].
The main cause of endemic goiter is iodine deficiency. For the last four decades, it has been thought that the reason for goiter development is the increased action of thyreotropin (TSH) on thyroid cell proliferation. During the last years, however, it became evident that local growth factors may be more directly involved in goiter formation and, furthermore, iodinated derivatives of membrane lipids are modulators of this growth factor's actions. TSH modulates both, the growth factor and growth factor receptor expression as well as the iodine content of the thyroid gland. In addition, most of the effects of TSH on thyroid volume seems to be the induction of thyroid hypertrophy, but not hyperplasia which is related to the action of local growth factors. These new insights in the pathophysiology of goiter development are important for the regimen of endemic goiter therapy. The current concept of goiter treatment by a TSH suppressive therapy has been derived from the previous hypothesis that TSH alone is more effective in causal goiter treatment than the TSH suppressive therapy.
Adolescent↗
Interleukin-1 beta (IL-1 beta) binds to intact porcine thyroid follicles, decreases iodide uptake but has no effect on cAMP formation or proliferation.
Interleukin-1 beta (IL-1 beta) is known to be involved in autoimmune thyroiditis. Since the results of different in vitro-studies on the effect of IL-1 on thyrocytes are controversial, our aim was to investigate the existence of specific binding sites for IL-1 beta and its influence on specific functions and growth of isolated porcine thyroid follicles ex vivo with a preserved iodide metabolism. For binding studies isolated thyroid follicles were incubated with 125I-IL-1 beta (213.5 nCi/ml) and with increasing concentrations of unlabelled IL-1 beta (0.06-11.5 nmol/l) for 24 h at 4 degrees C. The dissociation constant Kd was 0.85 x 10(-10) mol/l and about 800 binding sites per cell were calculated. IL-1 beta (10 U/ml) decreased basal and TSH-stimulated iodide uptake and organification after an incubation time of 45 min to 6 h without any influence on cAMP-formation. In addition, after 40 h of incubation IL-1 beta dose-dependently increased T3-secretion, followed by a decrease during simultaneous TSH-stimulation, whereas there was no effect on T4-secretion. In contrast to these functional effects IL-1 beta showed no influence on the growth of thyroid follicles, so that the cytokine cannot be made responsible for goiter growth in thyroid diseases by directly influencing thyroxytes.
Animals↗
Identification of delta-iodolactone in iodide treated human goiter and its inhibitory effect on proliferation of human thyroid follicles.
There is evidence that iodoarachidonates are mediators of iodide in thyroid autoregulation, however, their occurrence in vivo has not yet been demonstrated. We therefore tried to identify delta-iodolactone (5-Hydroxy-6-iodo-8,11,14-eicosatrienoic delta-lactone, IL-delta) in thyroid tissue from a patient with Graves' disease treated with high doses of iodide. Lipids were extracted from thyroid tissue, purified by reversed phase chromatography and analyzed by gas chromatography--tandem mass spectrometry (GC-MSMS). The retention time in gas chromatography and fragmentation pattern in tandem mass spectrometry were determined with biochemically synthesized non-deuterated and deuterated IL-delta. According to retention time (13.44 min) and specific fragments (m/z 303, m/z 259) the occurrence of IL-delta could be demonstrated in the extract of iodide treated goiter. In vitro, potassium iodide (40 microM) as well as IL-delta (1.0 microM) significantly inhibited the proliferation of human thyroid follicular cells induced by phorbol ester TPA (12-O-tetradecanoylphorbol 13-acetate). These results demonstrate for the first time that Il-delta is present in iodide treated human thyroid. As cell proliferation is under negative control of IL-delta, a crucial role in thyroid involution following iodide treatment may be possible.
Arachidonic Acids↗
Thyroxine treatment of benign goiter.
The conservative therapy of endemic as well as sporadic goiter is the TSH suppressive therapy with thyroxine. In the last decade, this therapeutic concept as well as the role of TSH in goiter development fell into disrepute. It has become evident that TSH mainly regulates thyroid function, induces hypertrophy of the follicular cells and increases the blood flow within the thyroid gland. The intrathyroidal iodine deficiency itself and the increased activity of local growth factors, however, may be the main causes of initiation, promotion and maintenance of hyperplasia. The clinical observation of a "shrinking" goiter during thyroxine therapy is now well established by ultrasound investigations as a decrease in goiter volume of maximal 30 to 40% within the first few months of treatment. Afterwards no further significant reduction in goiter size has been demonstrated so far. Stopping treatment results in an increase of goiter volume within a few weeks. These rapid changes can only be related to changes in the size of cells, follicles and vessels and not to growth or necrosis of thyroid cells. In comparison, treatment of endemic goiter with iodine also lead to a reduction of hypertrophy, but as demonstrated in rats, also to a reduction of hyperplasia. Treatment with iodine compared to thyroxine has a prolonged effect on reduction of goiter size even after withdrawal of the substitution. The main question that has to be discussed is whether the hyperplastic part of an endemic goiter in adults can be treated at all, either with thyroxine or iodine or both.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
[Controversies in the treatment of benign thyroid gland diseases].
Explore the source record for details and available documents.
Diagnosis, Differential↗
Isolation and partial molecular characterization of basic fibroblast growth factor from isolated porcine thyroid follicles and entire porcine thyroid glands.
Immunoreactive basic fibroblast growth factor (bFGF) could be isolated from the cytosol preparation of isolated porcine thyroid follicles as well as in the conditioned medium from thyroid follicles in suspension culture. A double band with 16,500 and 15,500 D was detected on sodium dodecyl sulfate polyacrylamide gel electrophoresis. In dot blot and western blot the isolated peptide was immunoreactive with a specific anti-bovine bFGF antibody. For further biochemical characterization, bFGF was isolated from entire porcine thyroid glands by ammonium sulfate precipitation, cation exchange chromatography and heparin affinity chromatography. The material obtained from all three origins was identical concerning affinity to heparin and immunoreactivity with the specific anti-bovine bFGF antibody and induced neovascularization in the chorioallantois membranes of chick embryos. Amino acid sequence analysis of the 16-amino-terminal amino acids of the isolated bFGF was in accordance with the established complete 146-amino-acid bFGF molecule except that glycine in position 10 is replaced by phenylalanine. An additionally identified minor peptide presumably is an amino-terminal-truncated form of bFGF, missing the first 15 amino acids. We conclude that the physiological significance of bFGF released by thyroid cells may be the regulation of angiogenesis during thyroid development and goiter growth.
Allantois↗
Thyroid growth in vitro.
Whereas there is no doubt about the role of the growth factors EGF (epidermal growth factor) and IGF I (insulin like growth factor I) on thyroid cell proliferation, controverse results have been obtained in different in vitro studies with TSH (thyrotropin). Whereas in nearly all cell culture systems using thyroid cell monolayers TSH enhances cell proliferation, TSH inhibits cell growth induced by EGF in intact thyroid follicles. These differences are not due to species specificity, because i.e. growth of porcine thyroid cells or of human thyroid cells in monolayer cultures is stimulated by TSH, but growth of human or porcine thyroid follicles is not stimulated by TSH. In addition there is some evidence that IGF I is necessary for the growth stimulating effect of TSH and IGF I seems to be an autocrine growth factor, which is under the control of TSH and/or iodine deficiency within the thyroid cell.
Animals↗
Role of autocrine and paracrine factors in thyroid follicle growth.
Basic fibroblast growth factor (bFGF), insulin like growth factor I and II and transforming growth factor beta (TGF-beta) are assumed to be of importance in the paracrine and autocrine regulation of thyroid growth and function. Using in vitro cultures of isolated intact porcine thyroid follicles, we here present data that support a possible autocrine action of bFGF on proliferation, a possible explanation for the observed potentiation of EGF-stimulated growth by IGF-I, and results on the release and regulation of release of TGF-beta. For growth experiments, thyroid follicles (2 x 10(5) cells) were incubated for 6 days followed by cell counting. For the analysis of EGF binding sites, follicles were preincubated with and without IGF-I (10 ng/mL) for 48 h at 37 degrees C, incubated with 125I-EGF (5 nCi/well) and unlabeled EGF (0.1-500 ng/mL) for 24 h at 4 degrees C (2 x 10(5) cells/well); binding characteristics were calculated from Scatchard analysis. The TGF-beta bioactivity in untreated and acid treated media conditioned with thyroid follicles for 3 days (2 x 10(7) cells) was analyzed with a bioassay using mink lung epithelial cells. Basic FGF (0.1-1 ng/mL) dose-dependently stimulated the proliferation of thyroid follicles up to 135.0 +/- 6.1%; this effect was additive with IGF-I (10 ng/mL) but not with EGF (2 ng/mL). The IGF-I (10 ng/mL) just moderately increased proliferation (128.3 +/- 16%), but potentiated EGF (1 ng/mL)-stimulated growth (from 183.0 +/- 11.0% to 314.0 +/- 3.0%).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
The role of iodine and thyroid cell growth.
The autoregulatory effects of iodide on thyroid growth and function are discussed to be mediated by iodinated derivatives of essential fatty acids (EFA), esp. iodolactones. We now reevaluated the effect of iodide on proliferation of isolated porcine thyroid follicles by determination of cell counts and investigated the effects of pretreatment of the follicles with arachidonic acid (AA, C 20:4 n6) in comparison to docosahexaenoic acid (DHA, C22:6 n3). Growth experiments were performed in multi-well culture plates and cell counts were determined after 6 d of incubation. EGF (5 ng/ml) significantly stimulated thyroid cell proliferation (151 +/- 6%; Mean +/- SD vs. basal control, 100 +/- 8%). 2.5 microM of iodide, added 24 h before EGF, had a weak stimulatory effect (168 +/- 9%) whereas higher concentrations of iodide (5-80 microM) exerted significantly dose-dependent inhibitory effects (117 +/- 1% at 80 microM of KI) which could be abolished with 500 microM of methimazole (155 +/- 11% at 80 microM of KI). Isolated porcine follicles showed a rapid uptake of EFA (25 microM) measured by specific tracer activity in the ethanol/acetic acid extracts of follicles (1.60 +/- 0.48 mumol EFA/ml follicle/24 h). Treatment with DHA (100 and 300 microM) significantly enhanced the inhibitory effect of 10 microM of iodide on thyroid follicle proliferation (84 +/- 2% and 45 +/- 4%) in contrast to follicles pretreated with AA (100 +/- 8% and 60 +/- 8%). These results demonstrate the biphasic effect of iodide on thyroid growth which can be abolished by inhibition of iodide organification with methimazole.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗