Hormonal Regulation of the MHC Class I Gene in Thyroid Cells: Role of the Promoter "Tissue-Specific" Region.

Cesidio Giuliani,Ines Bucci,Giorgio Napolitano,Sara Verrocchio,Fabio Verginelli,Antonino Grassadonia

doi:10.3389/fendo.2021.749609

Abstract

In previous studies we have demonstrated that the expression of the Major Histocompatibility Complex (MHC) class I gene in thyrocytes is controlled by several hormones, growth factors, and drugs. These substances mainly act on two regions of the MHC class I promoter a “tissue-specific” region (−800 to −676 bp) and a “hormone/cytokines-sensitive” region (−500 to −68 bp). In a previous study, we have shown that the role of the “tissue-specific” region in the MHC class I gene expression is dominant compared to that of the “hormone/cytokines-sensitive” region. In the present report we further investigate the dominant role of the “tissue-specific” region evaluating the effect of thyroid stimulating hormone (TSH), methimazole (MMI), phenylmethimazole (C10), glucose and thymosin-α1. By performing experiments of electrophoretic mobility shift assays (EMSAs) we show that TSH, MMI and C10, which inhibit MHC class I expression, act on the “tissue-specific” region increasing the formation of a silencer complex. Glucose and thymosin-α1, which stimulate MHC class I expression, act decreasing the formation of this complex. We further show that the silencer complex is formed by two distinct members of the transcription factors families activator protein-1 (AP-1) and nuclear factor-kB (NF-kB), c-jun and p65, respectively. These observations are important in order to understand the regulation of MHC class I gene expression in thyroid cells and its involvement in the development of thyroid autoimmunity.

Highlights

Several studies have demonstrated that Major histocompatibility complex (MHC) class I as well as class II overexpression on non-immune cells are important in the development of autoimmune diseases and thyroid autoimmunity [1,2,3,4,5,6,7,8,9]
electrophoretic mobility shift assays (EMSAs) Indicate That the Functional Effects of thyroid stimulating hormone (TSH), Glucose, Thymosin a-1, MMI and C10 on MHC Class I Gene Expression Correlate With Changes in Binding of DNA/Protein Complexes to the “Tissue-Specific” Region of the PD1 Promoter
Cellular extracts from cells cultured in 5H medium and 5% calf serum treated with compounds that cause a decrease of MHC class I expression, as MMI 5 mM, or C10 0.5 mM, or TSH 0.1 nM, showed an increase of the silencer complex (Figure 3A lanes 2, 3, 4 vs. 1, respectively; Table 3)

Summary

Introduction

Several studies have demonstrated that Major histocompatibility complex (MHC) class I as well as class II overexpression on non-immune cells are important in the development of autoimmune diseases and thyroid autoimmunity [1,2,3,4,5,6,7,8,9]. There is an increased expression of MHC class I and II molecules in pancreatic b islet cells of patients with type 1 diabetes mellitus, in muscle biopsies of patients with inflammatory myopathies, and in thyrocytes from patients with autoimmune thyroid. The same hormones and factors increase the transcription of thyroid specific genes that can act as potential autoantigens [7, 16, 17] These data assume a particular importance considering the possibility that innate immune activation can lead to an autoimmune response. Experiments conducted in FRTL-5 cells have shown that the release of genomic ds DNA by injury activate several genes involved in the immune response including the MHC class I gene [26] We think that this mechanism is true for other tissues expressing normally low levels of MHC class I molecules. Some further studies suggest that MHC class I overexpression is the trigger of immune-mediated myopathies [28, 29]

Methods

Results

Conclusion