MAJOR HISTOCOMPATIBILITY CLASS-II HLA-DR-ALPHA GENE-EXPRESSION IN THYROCYTES - COUNTER REGULATION BY THE CLASS-II TRANSACTIVATOR AND THE THYROID Y-BOX PROTEIN

Aberrant expression of major histocompatibility complex (MHC) class II proteins on thyrocytes; which is associated with autoimmune thyroid d isease, is mimicked by gamma-interferon (gamma-IFN). To define element s 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 t hat CIITA mimics the action of gamma-IFN. Thus, as is the case for gam ma-IFN, several distinct and highly conserved elements on the 5'-flank ing region of the HLA-DR alpha gene, the S, X-1, X-2, and Y boxes betw een -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 endogen ous CIITA transcript; pCIITA transfection mimics the ability of gamma- IFN treatment of FRTL-5 thyroid cells to increase the formation of a s pecific 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 expre ssion and increase complex formation is reduced by cotransfection of a thyroid Y box protein, which suppresses MHC class I gene expression i n FRTL-5 thyroid cells and is a homolog of human YB-1, which suppresse s MHC class II expression in human glioma cells. We conclude that CIIT A and TSH receptor suppressor element binding protein-1 are components of the gamma-IFN-regulated transduction system which, respectively, i ncrease or decrease class II gene expression in thyrocytes and may, th erefore, be involved in aberrant class II expression associated with a utoimmune thyroid disease.