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-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

Dugrillon A, Gärtner R. 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. Eur J Endocrinol 1995;132:735–43. ISSN 0804–4643

-Iodolactones (6-iodo-8,11,14-eicosatrienoic -lactone, -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 -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 µmol/l) as well as -IL (0.5–2 µmol/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 -IL, this may indicate a mechanism of -IL at or proximal to the calcium-dependent activation of protein kinase C. The growth inhibitory effect was restricted to -iodolactones when -Il was compared to 6-iodo-8,11,14,17-eicosatetraenoic -lactone and 5-iodo-7,10,13,16,19-docosapentaenoic -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 1.0U/l) revealing comparable kinetics in IP₃ generation, while cAMP formation was only stimulated by TSH, -Iodolactone (2 µmol/l) only decreased EGF-induced IP₃ formation, whereas TSH-induced IP₃ and cAMP formation was unchanged. The -iodolactone which did not inhibit thyroid cell proliferation, also had no effect on IP ₃ generation. These results demonstrate an action of iodide and -IL at the calcium-dependent signal transduction modulating thyroid cell proliferation by EGF but not TSH. -Iodolactone acts at or proximal to the generation of IP₃ induced by EGF, whereas the TSH-dependent signal transduction seems to be unaltered. -Iodolactone may therefore be speculated as a specific inhibitory mediator of iodide on growth factor-induced thyroid cell proliferation.

Alex Dugrillon, Zentrallabor der Medizinischen Klinik und Poliklinik, University of Heidelberg, Bergheimer Str. 58, D-69115 Heidelberg. Germany

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