TRANSFORMING GROWTH-FACTOR-BETA-1 SYNTHESIS IN HUMAN THYROID FOLLICULAR CELLS DIFFERENTIAL-EFFECTS OF IODIDE AND PLASMINOGEN ON THE PRODUCTION OF LATENT AND ACTIVE PEPTIDE FORMS

The present study has investigated the relative levels and interconversion of latent and active form of transforming growth factor-beta 1 (TGF-beta 1) in human thyroid follicular cell cultures derived from sporadic non-toxic goitres. Northern blotting of RNA extracted from 72-h cultures revealed a 2.5 kb mRNA transcript hybridizing with a cDNA probe for latent TGF-beta 1, the intensity of which was doubled in cells exposed to Nal (10 mu mol/l). Radioreceptor assay of follicular cell-conditioned medium for TGF-beta 1 content confirmed a similar enhancing effect of iodide. The endogenous active component of TGF-beta 1 present in conditioned medium represented only a minor fraction of the total TGF-beta 1 content, this fraction was not enhanced by exposure of follicular cells to iodide. The low level of endogenous active TGF-beta 1 in medium conditioned by either control or iodide-treated cells was confirmed by immunoadsorption with a precipitating antiserum against active TGF-beta 1, when such cells failed to show a reversal of the iodide-induced decrease in [methyl-H-3]thymidine incorporation into trichloroacetic acid-precipitable material. In contrast to the inhibitory effect of iodide on de novo DNA synthesis, which appeared not to reflect an increase in active TGF-beta 1, the inhibitory effects of plasminogen (100 mg/l) or plasmin (2000 U/l) on [methyl-H-3]thymidine incorporation into thyroid cells were reversible by TGF-beta 1 immunoadsorption. This provides evidence that the plasmin-mediated inhibition of DNA synthesis in thyroid follicular cells may be attributed to the growth-regulating action of an increased level of activated TGF-beta 1. The findings of this study therefore provide evidence that (i) human thyroid follicular cells are potentially capable of activating locally derived latent TGF-beta 1, (ii) an increase in thyroidal TGF-beta 1 mRNA and latent TGF-beta 1 peptide availability, following exposure of cells to iodide, is not accompanied by a corresponding increase in active TGF-beta 1, and (iii) within the thyroid gland, as in other epithelial tissues, activation of endogenous TGF-beta 1 may be dependent upon the proteolytic actions of plasmin.