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Endocrinology Vol. 139, No. 1 280-289
Copyright © 1998 by The Endocrine Society

ARTICLES

Major Histocompatibility Class II HLA-DR{alpha} Gene Expression in Thyrocytes: Counter Regulation by the Class II Transactivator and the Thyroid Y Box Protein

Valeria Montani1, Shin-ichi Taniguchi2, Minho Shong3, Koichi Suzuki, Masayuki Ohmori4, Cesidio Giuliani1,5, Giorgio Napolitano5, Motoyasu Saji1, Bruno Fiorentino, Andreas M. Reimold1, Jenny P.-Y. Ting, Leonard D. Kohn and Dinah S. Singer

Cell Regulation Section (V.M., S.-i.T., M.S., K.S., M.O., C.G., G.N., B.F., L.D.K.) Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases and Experimental Immunology Branch (D.S.S.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; Department of Surgery (M.S.), Johns Hopkins University, Baltimore, Maryland 21287; Departments of Cancer Biology and Medicine (A.M.R.), Harvard School of Public Health and Harvard Medical School, Boston, Massachusetts 02115; and Lineberger Comprehensive Cancer Research Center (J.P.-Y.T.), University of North Carolina, Chapel Hill, North Carolina 27599

Address all correspondence and requests for reprints to: Dr. Leonard D. Kohn, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Building 10, Room 9C101B, National Institutes of Health, Bethesda, Maryland 20892-1360. E-mail: lenk{at}bdg10.niddk.nih.gov

Aberrant expression of major histocompatibility complex (MHC) class II proteins on thyrocytes, which is associated with autoimmune thyroid disease, is mimicked by {gamma}-interferon ({gamma}-IFN). To define elements and factors that regulate class II gene expression in thyrocytes and that might be involved in aberrant expression, we have studied {gamma}-IFN-induced HLA-DR{alpha} gene expression in rat FRTL-5 thyroid cells. The present report shows that class II expression in FRTL-5 thyrocytes is positively regulated by the class II transactivator (CIITA), and that CIITA mimics the action of {gamma}-IFN. Thus, as is the case for {gamma}-IFN, several distinct and highly conserved elements on the 5'-flanking region of the HLA-DR{alpha} gene, the S, X1, X2, and Y boxes between -137 to -65 bp, are required for class II gene expression induced by pCIITA transfection in FRTL-5 thyroid cells. CIITA and {gamma}-IFN do not cause additive increases in HLA-DR{alpha} gene expression in FRTL-5 cells, consistent with the possibility that CIITA is an intermediate factor in the {gamma}-IFN pathway to increased class II gene expression. Additionally, {gamma}-IFN treatment of FRTL-5 cells induces an endogenous CIITA transcript; pCIITA transfection mimics the ability of {gamma}-IFN treatment of FRTL-5 thyroid cells to increase the formation of a specific and novel protein/DNA complex containing CBP, a coactivator of CRE binding proteins important for cAMP-induced gene expression; and the action of both {gamma}-IFN and CIITA to increase class II gene expression and increase complex formation is reduced by cotransfection of a thyroid Y box protein, which suppresses MHC class I gene expression in FRTL-5 thyroid cells and is a homolog of human YB-1, which suppresses MHC class II expression in human glioma cells. We conclude that CIITA and TSH receptor suppressor element binding protein-1 are components of the {gamma}-IFN-regulated transduction system which, respectively, increase or decrease class II gene expression in thyrocytes and may, therefore, be involved in aberrant class II expression associated with autoimmune thyroid disease.




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