δ-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

Abstract

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 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 delta-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 mumol/l) as well as delta-IL (0.5-2 mumol/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 delta-IL, this may indicate a mechanism of delta-IL at or proximal to the calcium-dependent activation of protein kinase C. The growth inhibitory effect was restricted to delta-iodolactones when delta-IL was compared to 6-iodo-8,11,14,17-eicosatetraenoic delta-lactone and 5-iodo-7,10,13,16,19-docosapentaenoic gamma-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 (1.0 U/l) revealing comparable kinetics in IP3 generation, while cAMP formation was only stimulated by TSH. delta-Iodolactone (2 mumol/l) only decreased EGF-induced IP3 formation, whereas TSH-induced IP3 and cAMP formation was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Relevance of iodine intake as a reputed predisposing factor for thyroid cancer

“…The iodolactone growth inhibitory mechanism, which is decreased in iodine-deficient thyroid cells, is believed to occur via inhibition of the specific EGFdependent production of IP3, a signal transducer that modulates thyroid cell proliferation (43). However, this compound had no effect on TSH-mediated cAMP formation in porcine follicles (43).…”

“…However, this compound had no effect on TSH-mediated cAMP formation in porcine follicles (43). Considered to be a more likely candidate is 2-iodohexadecanal (44), a major iodolipid formed in horse thyroid when incubated with iodide (45), but which is also detectable in the thyroid of other species, including humans and rats.…”

Inhibitory effects of 2-iodohexadecanal on FRTL-5 thyroid cells proliferation

“…Among these, 6-iodo-5-hydroxy-8,11,14-eicosatrienoic acid δ-lactone (IL δ) and 2-iodohexadecanal (2-IHDA) have been shown to inhibit several thyroid parameters and its participation in thyroid autoregulation has been suggested (Panneels et al, 2009). Moreover it was demonstrated that IL δ prevents goiter growth in rats (Pisarev et al, 1988 and that, in vitro, it inhibits thyroid cell proliferation in pigs (Dugrillon and Gärtner, 1995;Dugrillon et al, 1990), humans (Dugrillon et al, 1994) and FRTL-5 cells (Pisarev et al, 1992). Regarding 2-IHDA, in in vitro studies no growth suppressing effect could be demonstrated by measuring thymidine incorporation in primary cultures of dog thyroid cells (Panneels et al, 1994a) but we have demonstrated that it has an antigoitrogenic action (Thomasz et al, 2010a).…”

Iodide Effects on the Thyroid

“…Addition of the aldehyde 2-iodohexadecanal (2-IHDA) to thyroid slices and membranes reproduces two known XItype effects of iodide: the inhibition of adenylyl cyclase (Panneels et al, 1994b) and the inhibition of H 2 O 2 generation (Ohayon et al, 1994;Panneels et al, 1994a). Iodolactone at high concentrations inhibits the proliferation of porcine thyroid cells induced by EGF (Dugrillon and Gartner, 1995).…”