GENERAL INHIBITION BY TRANSFORMING GROWTH-FACTOR-BETA-1 OF THYROTROPIN AND CAMP RESPONSES IN HUMAN THYROID-CELLS IN PRIMARY CULTURE

Transforming growth factor beta1 (TGFbeta1) mRNA has previously been identified in human thyroid cells and this agent has been shown to inhibit DNA synthesis in thyroid cells of some other species. In normal human thyroid cells in primary culture, TGFbeta1 inhibited inconstantly the low basal DNA synthesis and strongly the stimulation of DNA synthesis by equine growth factor (EGF) and serum, and by thyroid-stimulating hormone (TSH) acting through cAMP. This inhibition, by TGFbeta1, of the TSH and cAMP-dependent DNA synthesis was associated with an inhibition of PCNA (proliferating cell nuclear antigen) synthesis. TGFbeta1 almost completely abolished the cAMP induced stimulation of iodide uptake and thyroperoxidase synthesis. It thus, like EGF, also acts as a dedifferentiating agent. Investigation of the pattern of protein synthesis by two-dimensional gel electrophoresis revealed that while TGFbeta1, by itself, increased the synthesis of only one protein, a tropomyosin isoform, it inhibited most of the effects of cAMP on protein synthesis (35 out of 45 cAMP-regulated proteins were affected). It also reversed the effect of cAMP on the morphology of the thyrocytes. The fact that TGFbeta1 did not affect the increase in cAMP provoked by TSH in human thyroid cells while inhibiting most of the effects of dibutyryl cAMP in these cells suggests an action at a step distal to cAMP generation. These data reemphasize the potentially major role of TGFbeta1 as a local modulator of the thyroid, showing for the first time that it inhibits both the growth and differentiation effects of TSH and cAMP on human thyroid cells.