title: Major histocompatibility class II HLA-DR alpha gene expression in thyrocytes: counter regulation by the class II transactivator and the thyroid Y box protein.
abstract: 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.
authors.affiliation: Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: V
authors.initials: V
authors.lastname: Montani
authors.forename: S I
authors.initials: SI
authors.lastname: Taniguchi
authors.forename: M
authors.initials: M
authors.lastname: Shong
authors.forename: K
authors.initials: K
authors.lastname: Suzuki
authors.forename: M
authors.initials: M
authors.lastname: Ohmori
authors.forename: C
authors.initials: C
authors.lastname: Giuliani
authors.forename: G
authors.initials: G
authors.lastname: Napolitano
authors.forename: M
authors.initials: M
authors.lastname: Saji
authors.forename: B
authors.initials: B
authors.lastname: Fiorentino
authors.forename: A M
authors.initials: AM
authors.lastname: Reimold
authors.forename: J P
authors.initials: JP
authors.lastname: Ting
authors.forename: L D
authors.initials: LD
authors.lastname: Kohn
authors.forename: D S
authors.initials: DS
authors.lastname: Singer
mesh_terms: D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D005786:Gene Expression Regulation; D005802:Genes, MHC Class II; D006684:HLA-DR Antigens / Q000235:genetics*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D051839:NFI Transcription Factors; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D051381:Rats; D013961:Thyroid Gland / Q000166:cytology / Q000378:metabolism*; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors; D051840:Y-Box-Binding Protein 1
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D006684:HLA-DR Antigens; C083728:MHC class II transactivator protein; D051839:NFI Transcription Factors; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; D007371:Interferon-gamma