POTENTIATION BY THYROID-HORMONE OF HUMAN IFN-GAMMA-INDUCED HLA-DR EXPRESSION

We have investigated the mechanism by which thyroid hormone potentiate s IFN-gamma-induced HLA-DR expression. IFN-gamma-induced KLA-DR expres sion requires activation of STAT1 alpha and induction of the Class II trans-activator, CIITA, HeLa and CV-1 cells treated only with L-thyrox ine (T-4) demonstrated increased tyrosine phosphorylation and nuclear translocation (= activation) of STAT1 alpha; this hormone effect on si gnal transduction, and T-4 potentiation of IFN-gamma-induced HLA-DR ex pression, were blocked by the inhibitors CGP 41251 (PKC) and genistein (tyrosine kinase), Treatment of cells with T-4-agarose also caused ac tivation of STAT1 alpha. In the presence of IFN-gamma, T-4 enhanced cy tokine-induced STAT1 alpha activation. Potentiation by T-4 of IFN-gamm a action was associated with increased mRNA for both CIITA and HLA-DR, with peak enhancement at 16 h (CIITA), and 2 d (HLA-DR). T-4 increase d IFN-gamma-induced HLA-DR protein 2.2-fold and HLA-DR mRNA fourfold a fter 2 d, Treatment with actinomycin D after induction of HLA-DR mRNA with IFN-gamma, with or without T-4, showed that thyroid hormone decre ased the t(1/2) of mRNA from 2.4 to 1.1 h, HeLa and CV-1 cells lack fu nctional nuclear thyroid hormone receptor. Tetraiodothyroacetic acid ( tetrac) and 3,5,3'-triiodo-thyroacetic acid (triac) blocked T-4 potent iation of IFN-gamma-induced HLA-DR expression and T-4 activation of ST AT1 alpha. These studies define an early hormone recognition step at t he cell surface that is novel, distinct from nuclear thyroid hormone r eceptor, and blocked by tetrac and triac, Thus, thyroid hormone potent iation of IFN-gamma-induced HLA-DR transcription is mediated by a cell membrane hormone binding site, enhanced activation of STAT1 alpha, an d increased CIITA induction.