Download PDF
Exp Clin Endocrinol Diabetes 2003; 111(6): 325-329
DOI: 10.1055/s-2003-42721
Article

J. A. Barth Verlag in Georg Thieme Verlag Stuttgart · New York

Influence of Iodide and Iodolactones on Thyroid Apoptosis

Evidence that Apoptosis Induced by Iodide is Mediated by Iodolactones in Intact Porcine Thyroid FolliclesR. Langer 1 , C. Burzler 2 , G. Bechtner 2 , R. Gärtner 2
  • 1Department of Pathology, Technische Universität München, Munich, Germany
  • 2Medizinische Klinik Innenstadt, Ludwig-Maximilians-Universität, Munich, Germany
Further Information

Publication History

Received: May 8, 2002 First decision: June 30, 2002

Accepted: March 13, 2003

Publication Date:
01 October 2003 (online)

Also available at
    Permissions and Reprints

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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 6 Burikhanov R B, Matsuzaki S. Excess iodine induces apoptosis in the thyroid of goitrogen-pretreated rats in vivo.  Thyroid. 2000;  10 123-129
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 9 Dugrillon A, Gärtner R. The role of iodine and thyroid cell growth.  Thyroidology Clin Exp. 1992;  4 31-36
    PubMedGoogle Scholar
  • 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Evan G, Littlewood T. A matter of life and cell death.  Science. 1998;  281 1317-1325
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 13 Fesus L, Davies P JA, Piacentini M. Apoptosis: Molecular mechanisms in programmed cell death.  Eur J Cell Biol. 1991;  56 170-177
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    Google Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 28 Savill J. .  Apoptosis in disease Eur J Endocrinol. 1994;  24 715-723
    PubMed
  • 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
    PubMedGoogle Scholar
  • 30 Steller H. Mechanisms and genes of cellular suicide.  Science. 1995;  267 1445-1449
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar

Prof. Dr. Roland Gärtner

Medizinische Klinik Innenstadt der Universität München

Ziemssenstr. 1

80336 München

Germany

Phone: + 498951602332

Fax: + 49 89 51 60 44 30

Email: rgartner@medinn.med.uni-muenchen.de

      >