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 proliferati on. It is discussed as a potential mediator of the autoregulatory path way of iodide in cyclic adenosine-3',5'-monophosphate (cAMP)- and thyr otropin (TSH)-independent growth. We therefore further localized the a ction of iodide and of delta-IL in isolated porcine thyroid follicles. Epidermal growth factor (EGF) and 12-O-tetradecanoylphorbol-13-acetat e (TPA) dose dependently stimulated thyroid cell proliferation, which could be inhibited by staurosporin (0.1-10 nmol/l). Iodide (2.5-40 mu mol/l) as well as delta-IL (0.5-2 mu mol/l) also dose dependently inhi bited EGF- and TPA-induced proliferation. As the calcium ionophor A(23 187) (100 pmol/l) completely abolished the inhibitory effects of iodid e and of delta-IL, this may indicate a mechanism of delta-IL at or pro ximal to the calcium-dependent activation of protein kinase C. The gro wth inhibitory effect was restricted to delta-iodolactones when delta- IL was compared to 6-iodo-8,11,14,17-eicosatetraenoic delta-lactone an d 5-iodo-7,10,13,16,19-docosapentaenoic gamma-lactone. It could not be prevented with propylthiouracil and therefore deiodination and a diff erent iodide action is unlikely. Inositol-1,4,5-trisphosphate (IP3) an d cAMP were measured in extracts from isolated porcine thyroid follicl es stimulated with EGF (10 ng/ml) or TSH (1.0 U/l) revealing comparabl e kinetics in IP3 generation, while cAMP formation was-only stimulated by TSH. delta-Iodolactone (2 mu mol/l) only decreased EGF-induced IP3 formation, whereas TSH-induced IP3 and cAMP formation was unchanged. The gamma-iodolactone, which did not inhibit thyroid cell proliferatio n, also had no effect on IP3 generation. These results demonstrate an action of iodide and delta-IL at the calcium-dependent signal transduc tion modulating thyroid cell proliferation by EGF but not TSH. delta-I odolactone acts at or proximal to the generation of IP3 induced by EGF , whereas the TSH-dependent signal transduction seems to be unaltered. delta-Iodolactone may therefore be speculated as a specific inhibitor y mediator of iodide on growth factor-induced thyroid cell proliferati on.