Potentiation by thyroid hormone of human IFN-gamma-induced HLA-DR expression.

We have investigated the mechanism by which thyroid hormone potentiates IFN-gamma-induced HLA-DR expression. IFN-gamma-induced HLA-DR expression requires activation of STAT1alpha and induction of the Class II trans-activator, CIITA. HeLa and CV-1 cells treated only with L-thyroxine (T4) demonstrated increased tyrosine phosphorylation and nuclear translocation (= activation) of STAT1alpha; this hormone effect on signal transduction, and T4 potentiation of IFN-gamma-induced HLA-DR expression, were blocked by the inhibitors CGP 41251 (PKC) and genistein (tyrosine kinase). Treatment of cells with T4-agarose also caused activation of STAT1alpha. In the presence of IFN-gamma, T4 enhanced cytokine-induced STAT1alpha activation. Potentiation by T4 of IFN-gamma action was associated with increased mRNA for both CIITA and HLA-DR, with peak enhancement at 16 h (CIITA), and 2 d (HLA-DR). T4 increased IFN-gamma-induced HLA-DR protein 2.2-fold and HLA-DR mRNA fourfold after 2 d. Treatment with actinomycin D after induction of HLA-DR mRNA with IFN-gamma, with or without T4, showed that thyroid hormone decreased the t(1/2) of mRNA from 2.4 to 1.1 h. HeLa and CV-1 cells lack functional nuclear thyroid hormone receptor. Tetraiodothyroacetic acid (tetrac) and 3,5,3'-triiodo-thyroacetic acid (triac) blocked T4 potentiation of IFN-gamma-induced HLA-DR expression and T4 activation of STAT1alpha. These studies define an early hormone recognition step at the cell surface that is novel, distinct from nuclear thyroid hormone receptor, and blocked by tetrac and triac. Thus, thyroid hormone potentiation of IFN-gamma-induced HLA-DR transcription is mediated by a cell membrane hormone binding site, enhanced activation of STAT1alpha, and increased CIITA induction.