While the multifunctional proteins of the transforming growth factor-beta (TGF-beta) family have a potent antiproliferative effect on thyroid follicular cell growth, increased expression of TGF-beta in proliferating thyroid cells and in thyroid tumours has recently been described, suggesting a secondary counter-regulatory role of these proteins. We have studied further this apparent paradox in vitro using FRTL-5 cells, 5 continuous cell strains from feline multinodular goitres (MNG) and 29 primary cultures prepared from human MNG. While dose dependent inhibition of FRTL-5 cell growth was confirmed, a variable fraction of these cells was naturally resistant towards TGF-beta 1, thus explaining the large interassay variability of growth inhibition (36 to 98% within 2 days, n = 19). After 40 days of continuous exposure, FRTL-5 cells became fully refractory towards TGF-beta 1 inhibition, due to the selective growth of naturally resistant subclones, as demonstrated for example by microscopic observation of three-dimensionally growing collagen-embedded cell clusters. The refractoriness could still be demonstrated even after several cell passages. In addition, 2 out of 5 feline thyroid cell strains obtained from feline MNG and 18 out of 29 primary cultures from human MNG showed a high degree of refractoriness towards TGF-beta. We conclude that constitutively TGF-beta resistant cells may occur in thyroid glands and that persistent TGF-beta refractoriness may secondarily be acquired. Resistant cells may escape regular growth control mechanisms and hence may contribute to the notorious heterogeneity of thyroid growth and to nodular transformation.
A small amount (3–4 per cent) of the homogenate of normal rat thyroid glands, labelled with radioiodine, resists enzymatic digestion by pancreatin and pronase and remains at the origin in alkaline and acid paper chromatography (»origin material«). Under certain conditions the pancreatin resistant compound can account for over 50 per cent of intrathyroidal iodine. The percentage of labelled origin material increases when the interval between single shot labelling and enzymatic digestion of the gland is extended to several days or weeks. The phenomenon is even more pronounced when the rats are kept on a low iodine diet (LID) during the whole experiment. Furthermore a relative increase of the labelled iodinated material occurs when rat thyroid glands are blocked with a thyrostatic drug or labelled to near isotopic equilibrium instead of short term labelling only. If the rats are kept on LID during the equilibration procedure, the relative concentration of origin material will again exceed that found in the thyroids of the control rats kept on HID. Autoradiography revealed that the centre of a PTU-blocked thyroid gland contains little radioactivity whereas large amounts of labelled colloid remain in the peripheral follicles. Mechanical separation of the peripheral layers from the thyroid core indicates that the enzyme resistant material is located mainly in hypcrplastic follicles. Ultracentrifugation studies have shown that the substance is heterogeneous. A small fraction is sedimented at low centrifugal speed, the bulk, however, remains in the supernatant and is of low molecular weight as shown by sucrose density centrifugation and sephadex gel filtration.
Evidence is presented that free iodide in the reaction medium during iodination of thyroglobulin by lactoperoxidase or thyroidperoxidase in vitro and a limiting Hz02 supply actively regulates the efficiency of the simultaneously occurring synthesis of iodothyronines. Our arguments are as follows.1. For any level of iodination achieved in vitro, the amount of iodine incorporated in newly formed iodothyronine residues (but not that of the overall iodination) was linearly and inversely correlated to the logarithm of free iodide remaining in the incubation medium. This finding holds true for iodide concentrations in the pM range, regardless of the native iodine content of a 19-S thyroglobulin sample, of the concentration of the enzymes and of the incubation time.2. When thyrogiobulins, iodinated either in the absence or in the presence of excess iodide, are compared the latter contained (for similar degrees of iodination) more newly synthesized diiodotyrosine residues but fewer iodothyronine residues, although over 50 "/, of these diiodotyrosine residues were hormonogenic.3. An additional important increase in hormone synthesis was obtained by extending the reaction time beyond the point were all iodide was organified. The latter phenomenon is but another demonstration that coupling always lags behind iodination.
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