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 microM and 20 microM) and iodolactone (0.05 microM and 0.5 microM), 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 microM iodide rapidly induced a rate of apoptosis (4 - 6 %) comparable to about 40-fold lower doses of delta-iodolactone (0.05 microM and 0.5 microM). 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 delta-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.

Molecular Iodine Induces Caspase-independent Apoptosis in Human Breast Carcinoma Cells Involving the Mitochondria-mediated Pathway

“…␣-Iodohexadecanal (alpha-IHDA) is a major iodolipid that has multiple inhibitory effects on adenylate cyclase, NADPH-oxidase, and thyroid peroxidase (52)(53)(54). Another iodolipid, 6-iodo-5-hydroxy-8,11,14-eicosatrienoic acid ⌬-lactone (⌬-iodolactone) is known to specifically inhibit signal transduction pathways induced by local growth factors, such as epidermal growth factor and basic fibroblast growth factor (55).…”

The role of iodine and δ-iodolactone in growth and apoptosis of malignant thyroid epithelial cells and breast cancer cells

“…Whereas the role of iodide and -iodolactone on growth inhibition and induction of apoptosis in normal thyroid follicular cells is well established, 8,12 no data are currently available for human thyroid carcinoma cells. Iodide as well as iodine had no effect on growth of carcinoma cells derived from anaplastic and follicular carcinoma.…”

“…This has already been demonstrated in normal porcine thyroid follicles ex vivo. 12 The MCF-7 cells express NIS only after incubation with all-trans Retinoic Acid (RA) or dexamethasone. 14 In our experiments, NIS was not induced by RA and there was no uptake of iodide (data not shown).…”

“…6 Iodine as well as -iodolactone also seems to induce apoptosis, and this might be the most important activity of iodine and -iodolactone, whereas -iodolactone seems to be the main active component. 12 It has also been shown that molecular iodine induces caspase-independent apoptosis in human breast carcinoma cells, involving the mitochondria-mediated pathway. 21 These experiments need to be done with -iodolactone for comparison.…”

“…11 We have also shown that both iodide and -iodolactone induce apoptosis, demonstrated by electron microscopy in porcine thyroid follicles ex vivo in a three-dimensional tissue culture. 12 Apoptosis was already induced by 0.05 µM of -iodolactone, whereas 20 µM of iodide were necessary to obtain a comparable effect. The effect of iodide was inhibited by methimazole in contrast to -iodolactone, indicating that peroxidase activity is necessary for the action of iodide on growth and apoptosis.…”