Abstract
The major histocompatibility complex (MHC) class I gene cAMP response element (CRE)-like site, -107 to -100 base pairs, is a critical component of a previously unrecognized silencer, -127 to -90 bp, important for thyrotropin (TSH)/cAMP-mediated repression in thyrocytes. TSH/cAMP induced-silencer activity is associated with the formation of novel complexes with the 38-base pair silencer, whose appearance requires the CRE and involves ubiquitous and thyroid-specific proteins as follows: the CRE-binding protein, a Y-box protein termed thyrotropin receptor (TSHR) suppressor element protein-1 (TSEP-1); thyroid transcription factor-1 (TTF-1); and Pax-8. TTF-1 is an enhancer of class I promoter activity; Pax-8 and TSEP-1 are suppressors. TSH/cAMP decreases TTF-1 complex formation with the silencer, thereby decreasing maximal class I expression; TSH/cAMP enhance TSEP-1 and Pax-8 complex formation in association with their repressive actions. Oligonucleotides that bind TSEP-1, not Pax-8, prevent formation of the TSH/cAMP-induced complexes associated with TSH-induced class I suppression, i.e. TSEP-1 appears to be the dominant repressor factor associated with TSH/cAMP-decreased class I activity and formation of the novel complexes. TSEP-1, TTF-1, and/or Pax-8 are involved in TSH/cAMP-induced negative regulation of the TSH receptor gene in thyrocytes, suppression of MHC class II, and up-regulation of thyroglobulin. TSH/cAMP coordinate regulation of common transcription factors may, therefore, be the basis for self-tolerance and the absence of autoimmunity in the face of TSHR-mediated increases in gene products that are important for thyroid growth and function but are able to act as autoantigens.
Highlights
From the ‡Cell Regulation Section, Metabolic Diseases Branch, NIDDKD and ¶Experimental Immunology Branch, NCI, National Institutes of Health, Bethesda, Maryland 20892
We suggested that TSH-decreased major histocompatibility complex (MHC) class I and TSH receptor (TSHR) gene expression might involve common transcription factors and that this allowed the cross-talk necessary for preserving selftolerance to gene products increased during TSHR-directed function and growth
MHC class I can be positively or negatively regulated in response to virus infections or lymphokines [54]; recently we showed that class I levels could be hormonally regulated and suggested this hormonal regulation might be important to suppress autoimmunity during hormonally induced changes in growth and function which resulted in altered levels of gene products known to be autoantigens (1, 2, 4 – 6)
Summary
Vol 272, No 32, Issue of August 8, pp. 20096 –20107, 1997 Printed in U.S.A. Regulation of Major Histocompatibility Complex Class I Gene Expression in Thyroid Cells. TSH/cAMP induced-silencer activity is associated with the formation of novel complexes with the 38-base pair silencer, whose appearance requires the CRE and involves ubiquitous and thyroid-specific proteins as follows: the CRE-binding protein, a Y-box protein termed thyrotropin receptor (TSHR) suppressor element protein-1 (TSEP-1); thyroid transcription factor-1 (TTF-1); and Pax-8. TSH/cAMP coordinate regulation of common transcription factors may, be the basis for self-tolerance and the absence of autoimmunity in the face of TSHR-mediated increases in gene products that are important for thyroid growth and function but are able to act as autoantigens. Since enhanced class I expression has been demonstrated in thyrocytes from patients with autoimmune thyroid disease (ATD) [3], we proposed (1, 2, 4 – 6) that TSH suppression of class I levels might be a normal mechanism to preserve self-tolerance in the face of increases in gene products associated with growth and function and that its loss or attenuation might cause ATD. We show that TSH/cAMP-induced suppression of the class I, TG, and TSHR genes involves common transcription factors, as hypothesized (1, 2, 4 – 6)
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