Influence of Iodide and Iodolactones on Thyroid Apoptosis

Abstract

Iodine induced thyroid involution is caused by apoptosis rather than necrosis. This effect of iodide on apoptosis of thyroid epithelial cells may be not a direct one but mediated by iodinated derivatives i.e. of polyunsaturated fatty acids, especially of iodolactones, which have previously shown to inhibit thyroid cell proliferation. We studied the influence on apoptosis of iodide (2 µM and 20 µM) and iodolactone (0.05 µM and 0.5 µM), with and without TSH (1 mU/ml), using a well characterized ex vivo- culture system of intact porcine thyroid follicles in three-dimensional culture. Apoptosis and necrosis was evaluated by electron-microscopy.

Stimulation with 2 and 20 µM iodide rapidly induced a rate of apoptosis (4 - 6 %) comparable to about 40-fold lower doses of δ-iodolactone (0.05 µM and 0.5 µM). Addition of TSH (1 mU/ml) caused a slight but not significant further increase of the incidence of apoptotic cells. The rate of necrotic thyroid epithelial cells (1 - 2 %) was similar in all experiments.

As δ-iodolactone in very low concentrations - comparable to iodide in higher concentrations - not only inhibits growth but also induces apoptosis, it has to be supposed that the effect of iodide is mediated by this iodinated compound. However, further experiments are necessary to confirm this hypothesis. In addition it could be demonstrated, that apoptosis is a very rapid and limited process in intact follicles. This also may explain, why iodine supplementation even in high doses does not lead to thyroid atrophy but only normalisation of thyroid size. These results confirm that apoptosis is an important regulated and limited mechanism in goiter involution.

Key words

Apoptosis - iodide - iodolactones - thyroid

References

• 1 Basolo F, Pollina L, Fontanini G, Fiore L, Pacini F, Baldanzi A. Apoptosis and proliferation in thyroid carcinoma: correlation with bcl-2 and p53 protein expression.  Brit J Cancer. 1997;  75 537-541
• 2 Bechtner G, Fröschl H, Sachse A, Schopohl D, Gärtner R. Induction of apoptosis in porcine thyroid follicles by transforming growth factor β1 and epidermal growth factor.  Biochimie. 1999;  81 315-320
• 3 Bechtner G, Schopohl D, Rafferzeder M, Gärtner R, Welsch U. Stimulation of thyroid cell proliferation by epidermal growth factor is different from cell growth induced by thyrotropin or insulin-like growth factor I.  Eur J Endocrinol. 1996;  134 639-648
• 4 Bogerson K L, Bretz J D, Baker jr J R. The role of Fas-mediated apoptosis in thyroid autoimmune disease.  Autoimmunity. 1999;  30 251-264
• 5 Bretz J D, Rymaszewiski M, Arscott P L, Myc A, Ain K B, Thompson N W, Baker J R. Inflammatory cytokines regulation of Fas-mediated apoptosis in thyroid follicular cells.  J Biol Chem. 1999;  274 23627-23632
• 6 Burikhanov R B, Matsuzaki S. Excess iodine induces apoptosis in the thyroid of goitrogen-pretreated rats in vivo.  Thyroid. 2000;  10 123-129
• 7 Dugrillon A, Bechtner G, Uedelhoven W M, Weber P C, Gärtner R. Evidence that an iodolactone mediates the inhibitory effect of iodide on thyroid cell proliferation but not on adenosine 3′0, 5′-monophos-phate formation.  Endocrinology. 1990;  127 337-343
• 8 Dugrillon A, Gärtner R. δ-Iodolactones decrease epidermal growth-factor induced proliferation and inositol-1, 4, 5-triphosphate generation in porcine thyroid follicles - a possible mechanism of growth inhibition by iodide.  Eur J Endocrinol. 1995;  132 735-743
• 9 Dugrillon A, Gärtner R. The role of iodine and thyroid cell growth.  Thyroidology Clin Exp. 1992;  4 31-36
• 10 Dugrillon A, Uedelhoven W M, Pisarev M A, Bechtner G, Gärtner R. Identification of δ-iodolactone in iodide treated human goiter and its inhibitory effect on proliferation of human thyroid follicles.  Horm Metab Res. 1994;  26 465-469
• 11 Evan G, Littlewood T. A matter of life and cell death.  Science. 1998;  281 1317-1325
• 12 Feldkamp J, Pascher E, Perniok A, Scherbaum W A. Fas-Mediated apoptosis is inhibited by TSH and iodine in moderate concentrations in primary human thyrocytes in vitro.  Horm Metab Res. 1999;  31 355-358
• 13 Fesus L, Davies P JA, Piacentini M. Apoptosis: Molecular mechanisms in programmed cell death.  Eur J Cell Biol. 1991;  56 170-177
• 14 Gärtner R, Greil W, Stübner D, Permanetter W, Horn K, Pickardt C R. Preparation of porcine thyroid follicles with preserved polarity: functional and morphological properties in comparison to inside-out follicles.  Mol Cell Endocrinol. 1985;  40 9-16
• 15 Gärtner R, Schopohl D, Schaeffer S, Dugrillon A, Erdmann A, Toda S, Bechtner G. Regulation of transforming growth factor β1 messenger ribonucleic acid expression in porcine thyroid follicles in vitro by growth factors, iodine or δ-iodolactone.  Thyroid. 1997;  7 633-640
• 16 Hintze G, Emrich D, Köbberling J. Treatment of endemic goiter due to iodine deficiency with iodine, levothyroxine or both: results of a multicentre trial.  Eur J Clin Invest. 1989;  12 209-220
• 17 Hirmomatsu Y, Hoshino T, Yagita H, Koga M, Sakisaka S, Honda J, Yang D, Kayagaki N, Okumura K, Nonaka K. Functional Fas ligand expression in thyrocytes from patients with Grave's disease.  J Clin Endocrinol Metab. 1999;  84 2896-2902
• 18 Knauf J A, Elisei R, Mochly-Rosen D, Liron T, Chen X N, Gonsky R, Korenberg J R, Fagin J A. Involvement of protein kinase C epsilon (PK C epsilon) cloned from a thyroid cancer cell line protects thyroid cells from apoptosis.  J Biol Chem. 1999;  274 23414-23425
• 19 Koga M, Hiromatsu Y, Jimi A, Toda S, Koike N, Nonaka K. Immunohistochemical analysis of Bcl-2, Bax, and Bak expression in thyroid glands from patients with subacute thyroiditis.  J Clin Endocrinol Metab. 1999;  84 2221-2225
• 20 Kotani T, Aratake Y, Hirai K, Fukazawa Y, Sato H, Ohtaki S. Apoptosis in thyroid tissue from patients with Hashimoto's thyroiditis.  Autoimmunity. 1995;  20 231-236
• 21 Labat-Moleur F, Chabre O, Guillermet C, Chaffanjon P, Blumet-Rondeu F, Bauchet A, Franc B, Brambilla E, Bachelot I, Dumont J E, Negoescu A. Graves-Basedow disease goiter: a model of Bax-Bcl2 regulated apoptosis.  Thyroid. 1999;  9 483-492
• 22 Mitsiades N, Poulaki V, Kotoula V, Mastorakos G, Tseleni-Balafouta S, Koutras D A, Tsokos M. Fas/Fas ligand up-regulation and Bcl-2 down-regulation may be significant in the pathogenesis of Hashimoto's thyroiditis.  J Endocrinol Metab. 1998;  83 2199-2203
• 23 Moore D, Ohene-Fianko D, Garcia B, Chakrabarti S. Apoptosis in thyroid neoplasms: relationship with p53 and bcl-2 expression.  Histopathology. 1998;  32 35-42
• 24 Patel V A, Hill D J, Sheppard M C, Wang F, Logan A, Eggo M C. Apoptosis during goitre involution - the role of Bcl-2.  J Endocrinol. 2000;  164 323-330
• 25 Riesco J M, Juanes J A, Carretero J, Blanco E J, Riesco-Lopez J M, Vasques G, Vasques R. Cell proliferation and apoptosis of thyroid follicular cells are involved in the involution of experimental non-tumoral hyperplastic goiter.  Anat Embryol. 1998;  198 439-450
• 26 Riou C, Remy C, Rabilloud R, Rousset B, Fonlupt P. H2O2 induces apoptosis of pig thyrocytes in culture.  J Endocrinol. 1998;  156 315-322
• 27 Riou C, Tonoli H, Bernier-Valentin F, Rabilloud R, Fonlupt P, Rousset B. Susceptibiliy of differentiated thyrocytes in primary culture to undergo apoptosis after exposure to hydrogen peroxide: relation with the level of expression of apoptosis regulatory proteins, Bcl-2 and Bax.  Endocrinology. 1999;  140 1990-1997
• 28 Savill J. .  Apoptosis in disease Eur J Endocrinol. 1994;  24 715-723
• 29 Sreelekha T T, Pradeep V M, Vijayalakshmi K, Belthazar A, Chellam V G, Nair M B, Pillai M R. In situ apoptosis in the thyroid.  Thyroid. 2000;  10 117-122
• 30 Steller H. Mechanisms and genes of cellular suicide.  Science. 1995;  267 1445-1449
• 31 Stübner D, Gärtner R, Greil W, Gropper K, Brabant G, Permanetter W, Horn K, Pickardt C R. Hypertrophy and hyperplasia during goiter growth and involution in rats-seperate bioeffects of TSH and iodine.  Acta Endocrinol. 1987;  116 537-548
• 32 Tamura M, Kimura H, Koji T, Tominaga T, Ashizawa K, Kiriyama T, Yokoyama N, Yoshimura T, Eguchi K, Nakane P, Nagataki S. Role of apoptosis of thyrocytes in a rat model of goiter. A possible involvement of Fas system.  Endocrinology. 1998;  8 3646-3653
• 33 Vitale M, Di Matola T, D'Ascoli F, Salzano S, Bogazzi F, Fenzi G, Martino E, Rossi G. Iodide excess induces apoptosis in thyroid cells through a p53-independent mechanism involving oxidative stress.  Endocrinology. 2000;  141 598-605
• 34 Williams G T, Smith C A, McCarthy N J, Grimes E A. Apoptosis: Final control point in cell biology.  Trends Cell Biol. 1992;  2 263-267
• 35 Yoshida A, Nakamura Y, Imada T, Asaga T, Shimizu A, Harada M. Apoptosis and proliferative activity in thyroid tumors.  Surgery Today. 1999;  29 204-208