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C Giuliani, University "G. DAnnunzio" Chieti, Unit of Endocrinology, Chieti, Italy
I Bucci, University "G. D'Annunzio" Chieti, Unit of Endocrinology, Chieti, Italy
V Montani, University "G. D'Annunzio" Chieti, Unit of Endocrinology, Chieti, Italy
D Singer, National Institutes of Health, Experimental Immunology Branch, National Cancer Institute, Bethesda, United States
F Monaco, University "G. D'Annunzio" Chieti, Unit of Endocrinology, Chieti, Italy
L Kohn, Ohio University, Dept of Biomedical Sciences, College of Osteopathic Medicine, Athens, United States
G Napolitano, University "G. D'Annunzio" Chieti, Unit of Endocrinology, Chieti, Italy

Correspondence: Cesidio Giuliani, Email: cgiulian{at}unich.it

Increased expression of major histocompatibility complex (MHC) class-I genes and aberrant expression of MHC class-II genes in thyroid epithelial cells (TECs) is associated with autoimmune thyroid diseases. Previous studies have shown that methimazole (MMI) reduces MHC class-I expression and inhibits interferon- (IFN-)-induced expression of the MHC class-II gene in TECs. The action of MMI on the MHC class-I gene is transcriptional, but its mechanism has not been previously investigated. In the present study, we show that in Fisher rat thyroid cell line 5 (FRTL-5) cells, the ability of MMI and its novel derivative phenylmethimazole (C10) to decrease MHC class-I promoter activity is similar to TSH/cAMP suppression of MHC class-I and TSH receptor genes, and involves a 39-bp silencer containing a CRE-like site. Furthermore, we show that C10 decreases MHC class-I gene expression to a greater extent than MMI and at 10-fold to 50-fold lower concentrations. C10 also reduces the IFN--induced increase in the expression of MHC class-I and MHC class-II genes more effectively than MMI. Finally, we show that in comparison to MMI, C10 is a better inhibitor of specific protein-DNA complexes that are formed with a CRE-like element on the MHC class-II promoter. These data support the conclusion that the immunosuppressive mechanism by which MMI and C10 inhibit MHC gene expression mimics "normal" hormonal suppression by TSH/cAMP.