Interferon-gamma inhibition of human thyrotropin receptor gene expression

To evaluate the role of interferon-gamma (IFN gamma) on human thyroid-specific gene expression, the effect of IFN gamma on TSH- and cAMP-induced TSH receptor gene expression was studied using cultured thyroid cells obtained from normal thyroid glands and those from patients with Graves' disease. Incubation of Graves' thyroid cells with 1.0 U/L bovine TSH or 1.0 mM 8-bromo-cAMP resulted in a 2-fold increase in TSH receptor mRNA expression, which was markedly inhibited in the presence of IFN gamma in a dose- and time-dependent manner. This inhibitory effect was completely neutralized by monoclonal antibody against IFN gamma. IFN alpha and -beta had no influence on TSH- and cAMP-stimulated TSH receptor mRNA expression. Paranodular normal thyroid cells showed the same results as those obtained using Graves' thyroid cells. Scatchard analysis of the [125I]TSH binding study showed that IFN gamma inhibited the number of TSH receptors up-regulated by TSH on the cell surface at the low affinity binding site (4.1 vs. 8.2 x 10(5)/cell). These results indicate that IFN gamma suppresses TSH- and cAMP stimulated human TSH receptor gene expression, resulting in a decrease in the number of TSH receptors. In conclusion, IFN gamma interacts via an intermediate pathway of TSH signal transduction and attenuates TSH receptor synthesis in normal and Graves' thyroid cells.