Hormonal regulation of major histocompatibility complex class I genes in rat thyroid FRTL-5 cells: thyroid-stimulating hormone induces a cAMP-mediated decrease in class I expression.

Abstract

Thyrocytes normally express major histocompatibility complex (MHC) class I, but not class U, cell surface antigens. A rat thyrocyte cell line, FRTL-5, also expresses MHC class I antigens, in addition to a variety of thyroid-specific genes. Treatment of FRTL-5 thyrocytes with physiological concentrations of thyroid-stimulating hormone (TSH) has been shown to induce increased expressed of thyroglobulin and thyroid peroxidase but to simultaneously decrease expression of the TSH receptor. The reduction in TSH receptor expression by TSH is cAMP mediated. In the present study, it is demonstrated that, in thyrocytes treated with TSH, MHC class I expression decreases concomitant with the decrease in TSH receptor expression. This decreased expression is evidenced by reduced cell surface levels of MHC class I antigens, by reduced steady-state RNA levels, and by reduced transcription of the class I genes. TSH-mediated reduction of MHC class I gene transcription in FRTL-5 cells was mapped to a region within 135 base pairs of the promoter.Many of the human thyroid diseases, including Graves and Hashimoto, appear to be autoimmune diseases. As a result, the roles of the major histocompatibility (MHC) class I and class II cell surface molecules in the etiology ofthese diseases have been examined extensively (1-10). Both class I and class II molecules are glycoproteins that play pivotal roles in the induction and propagation of immune responses (11-13). The MHC class I molecules function primarily as the targets of the cellular immune response, whereas the class II molecules regulate both the humoral and cellular immune responses. In Graves disease and autoimmune thyroiditis, both class I and class II cell surface levels have been shown to be elevated. Although there have been extensive studies on the factors regulating class II expression in thyrocytes, including the rat FRTL-5 thyroid cell model (5-10), less attention has been focused on the patterns of expression of MHC class I molecules.Thyroid-stimulating hormone (TSH) has pleiotropic effects on thyrocytes: induction of thyroglobulin (Tg) and thyroid peroxidase (TPO) mRNA and protein, increased iodide uptake, and generation and secretion of the thyroid hormones T3 and T4 (14). TSH also regulates TSH receptor (TSHr) gene transcription, but by a complex process. Thus, in the functioning rat FRTL-5 cell, TSH induces an initial transient increase in TSHr RNA levels followed by a significant reduction in TSHr gene transcription concomitant with its stimulation ofTg, TPO,. The TSHr response to TSH, like those of Tg and TPO, has been demonstrated to be mediated primarily by cAMP (16,17).In the present study, we have investigated TSH regulation of expression of MHC class I genes in thyrocytes and report that class I genes are expressed in these cells and that expression is reduced by TSH. The TSH-induced decrease in expression is dependent on the presence of the TSHr, is cAMP-mediated, and is transcriptional. TSH-mediated reduction of class I transcription is mapped to a ...

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