Effects of interleukins on EGF-stimulated growth promotion in human thyroid cells: differential modifications by IL-2 and IL-6 in Graves' and normal thyroid cells.

To investigate the role of interleukins on the growth of human thyroid cells, the effect of IL-2, IL-4 and IL-6 was studied on EGF-induced [3H]-thymidine uptake, cell cycle by flow cytometry, and mRNA levels of cellular proto-oncogene c-fos in thyroid monolayer cells from eighteen patients with Graves' disease and sixteen with non-thyroidal disease. EGF stimulated the DNA synthesis and the expression of c-fos mRNA both in Graves' thyroid cells and in normal thyroid cells. A dose-dependent inhibition of Graves' thyroid cell growth was observed with increasing concentration of IL-2 regardless of coculture with EGF. IL-2 did not influence [3H]-thymidine uptake nor the percentage of S+G2/M phase in cell cycle in normal thyroid cells. Such effects were not modified by the elimination or addition of lymphocytes. IL-2 did not affect the EGF-induced expression of c-fos mRNA in both Graves' and normal thyroid cells. IL-6 (10(-2)-10 ng/ml) stimulated the [3H]-thymidine uptake up to 218-303 % of control level, and the percentage of cells in S+G2/M phase was increased in IL-6-treated normal thyroid cells as compared to EGF-treated cells. IL-6 did not augment these parameters in Graves' thyroid cells. When EGF was included with IL-6, the level in c-fos mRNA was further augmented in normal thyroid cells. Such an additive effect was not seen in Graves' thyroid cells. Incubation of Graves' or normal thyroid cells with IL-4 did not affect the [3H]-thymidine uptake nor the percentage of S+G2/M. These data suggest that, compared with normal cells, the growth factors (such as cytokines), may act in an opposite way in Graves' thyroid cells. The different behavior between Graves' and normal thyroid cells in response to IL-2 and IL-6 might contribute to the pathogenesis of goiter formation.