Regulation of major histocompatibility complex gene expression in thyroid epithelial cells by methimazole and phenylmethimazole.
Increased expression of major histocompatibility complex (MHC) class-I genes and aberrant expression of MHC class-II genes in thyroid epithelial cells (TECs) are associated with autoimmune thyroid diseases. Previous studies have shown that methimazole (MMI) reduces MHC class-I expression and inhibits interferon-gamma (IFN-gamma or IFNG as listed in the MGI Database)-induced expression of the MHC class-II genes in TECs. The action of MMI on the MHC class-I genes is transcriptional, but its mechanism has not been investigated previously. In the present study, we show that in Fisher rat thyroid cell line 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 cAMP response element (CRE)-like site. Furthermore, we show that C10 decreases MHC class-I gene expression to a greater extent than MMI and at 10- to 50-fold lower concentrations. C10 also reduces the IFN-gamma-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.
Giuliani
Cesidio
C
Unit of Endocrinology, Department of Medicine and Sciences of Aging, University G. D'Annunzio, Aging Research Center (Ce.S.I.), Gabriele D'Annunzio University Foundation, via Colle dell'Ara, Chieti-Pescara, 66013 Chieti, Italy. cgiulian@unich.it
Bucci
Ines
I
Montani
Valeria
V
Singer
Dinah S
DS
Monaco
Fabrizio
F
Kohn
Leonard D
LD
Napolitano
Giorgio
G
D000818:Animals; D013956:Antithyroid Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D004247:DNA; D004847:Epithelial Cells / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects*; D020868:Gene Silencing; D005805:Genes, MHC Class I; D005802:Genes, MHC Class II; D007371:Interferon-gamma / Q000494:pharmacology; D008713:Methimazole / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins; D020218:Response Elements; D013871:Thiones / Q000008:administration & dosage / Q000494:pharmacology*; D013961:Thyroid Gland / Q000378:metabolism*; D024363:Transcription Initiation Site
D013956:Antithyroid Agents; D011994:Recombinant Proteins; D013871:Thiones; C489637:phenyl methimazole; D008713:Methimazole; D007371:Interferon-gamma; D004247:DNA; D000242:Cyclic AMP