Molecular Endocrinology, Vol 10, 826-836, Copyright © 1996 by Endocrine Society

ARTICLES

Interferon-gamma suppresses thyrotropin receptor promoter activity by reducing thyroid transcription factor-1 (TTF-1) binding to its recognition site

K Ohe, S Ikuyama, R Takayanagi, LD Kohn and H Nawata
Third Department of Internal Medicine, Kyushu University Faculty of Medicine, Fukuoka, Japan.

Interferon-gamma (IFN gamma) is known to suppress the expression of thyroid-specific genes, such as thyroglobulin, thyroid peroxidase, and the TSH receptor (TSHR). In the present study, we show that this reflects, in part, a transcriptional action mediated by thyroid transcription factor-1 (TTF-1). Thus, transfected into rat FRTL-5 cells, the activity of reporter plasmids, containing rat TSHR promoter ligated to a chloramphenicol acetyltransferase gene, was significantly suppressed in the presence of rat IFN gamma. A -199-bp promoter construct showed the greatest suppression by IFN gamma whereas a -177- bp construct, in which the TTF-1 binding site was deleted, showed less suppressibility. The suppressive effect was rat IFN gamma-specific, since human IFN alpha, -beta, and -gamma exhibited no significant effects. The effect was concentration-dependent from 3-50 U/ml. In FRT rat thyroid cells that do not express TTF-1, IFN gamma-induced suppression on the promoter activity was not observed. In addition, when the TTF-1 binding site was mutated so that TTF-1 can not bind, IFN gamma-induced suppression was significantly reduced. In gel mobility shift analyses, a protein-DNA complex formed by TTF-1 was reduced when the nuclear extract prepared from IFN gamma-treated FRTL-5 cells was used; however, expression of TTF-1 mRNA and TTF-1 protein, which were assessed by Northern blot analysis and Western blot analysis, respectively, were not affected by IFN gamma treatment of FRTL-5 cells. Instead, reduction of DNA-binding affinity of TTF-1 was evident when competition analysis was performed in gel mobility shift analysis. From these results, we conclude that IFN gamma suppresses TSHR promoter activity, in part, by reducing TTF-1 binding to its recognition site. We also raise the possibility that the suppressive effect of IFN gamma on promoter activity is mediated by additional element(s) and factor(s) downstream of the TTF-1 site.

This article has been cited by other articles:

				A.-C. Gerard, M. Boucquey, M.-F. van den Hove, and I. M. Colin Expression of TPO and ThOXs in human thyrocytes is downregulated by IL-1{alpha}/IFN-{gamma}, an effect partially mediated by nitric oxide Am J Physiol Endocrinol Metab, August 1, 2006; 291(2): E242 - E253. [Abstract] [Full Text] [PDF]

				M. Ohmori, N. Harii, T. Endo, and T. Onaya Tumor Necrosis Factor-{alpha} Regulation of Thyroid Transcription Factor-1 and Pax-8 in Rat Thyroid FRTL-5 Cells Endocrinology, October 1, 1999; 140(10): 4651 - 4658. [Abstract] [Full Text]

				A. Miyazaki, H. Shimura, T. Endo, K. Haraguchi, and T. Onaya Tumor Necrosis Factor-{alpha} and Interferon-{gamma} Suppress Both Gene Expression and Deoxyribonucleic Acid-Binding of TTF-2 in FRTL-5 Cells Endocrinology, September 1, 1999; 140(9): 4214 - 4220. [Abstract] [Full Text]

				P. L. Balducci-Silano, K. Suzuki, M. Ohta, J. Saito, M. Ohmori, V. Montani, G. Napolitano, M. Shong, S.-I. Taniguchi, M. Pietrarelli, et al. Regulation of Major Histocompatibility (MHC) Class II Human Leukocyte Antigen-DR{alpha} Gene Expression in Thyrocytes by Single Strand Binding Protein-1, a Transcription Factor That Also Regulates Thyrotropin Receptor and MHC Class I Gene Expression Endocrinology, May 1, 1998; 139(5): 2300 - 2313. [Abstract] [Full Text] [PDF]

				A. S. Kumar, V. C. Venkatesh, B. C. Planer, S. I. Feinstein, and P. L. Ballard Phorbol Ester Down-regulation of Lung Surfactant Protein B Gene Expression by Cytoplasmic Trapping of Thyroid Transcription Factor-1 and Hepatocyte Nuclear Factor 3 J. Biol. Chem., August 15, 1997; 272(33): 20764 - 20773. [Abstract] [Full Text] [PDF]

				P. Caturegli, M. Hejazi, K. Suzuki, O. Dohan, N. Carrasco, L. D. Kohn, and N. R. Rose Hypothyroidism in transgenic mice expressing IFN-gamma in the thyroid PNAS, February 15, 2000; 97(4): 1719 - 1724. [Abstract] [Full Text] [PDF]