POTENTIATION BY THYROXINE OF INTERFERON-GAMMA-INDUCED HLA-DR EXPRESSION IS PROTEIN-KINASE A-DEPENDENT AND C-DEPENDENT

L-Thyroxine (T-4) and 3,3',5-L-triiodothyronine (T-3) potentiate the a ntiviral state induced by interferon-gamma (IFN-gamma) in homologous c ells by a mechanism that is dependent upon calcium/phospholipid-depend ent protein kinase (PKC), L-T-4 and T-3 also potentiate induction by I FN-gamma of MHC class II HLA-DR antigen expression in HeLa cells, In t he present studies of HLA-DR expression, the PKC inhibitor staurospori ne (0.1-1 nM) enhanced the expression of HLA-DR when the inhibitor was added simultaneously with IFN-gamma, 100 IU/ml, In the presence of IF N-gamma and 10(-7) M T-4, the same concentrations of staurosporine inh ibited potentiation of HLA-DR expression by thyroid hormone, A more sp ecific PKC inhibitor, CGP41251 (0.5-5 nM), similarly enhanced HLA-DR e xpression in the presence of IFN-gamma but inhibited thyroid hormone p otentiation of antigen expression, Both actions of CGP41251 were suppr essed when cells were also treated with phorbol 12-myristate 13-acetat e (PMA). A phospholipase C inhibitor, U73122 (1-1000 nM), did not alte r the potentiating ability of T-4, although it inhibited in a concentr ation-dependent manner the expression of HLA-DR induced by IFN-gamma. The potentiating effect of T-4 was much more sensitive to a cyclic AMP -dependent protein kinase (PKA) inhibitor, KT5720 (1-1000 nM), than wa s the induction of HLA-DR by IFN-gamma. The inhibitory effects of KT57 20 were reversed by concurrent 8-bromo-cAMP treatment, The calmodulin antagonist W-7 (5-50 mu M) did not alter IFN-gamma induction of HLA-DR in either the presence or absence of T-4. HLA-DR expression in HeLa c ells appears to be under PKC-associated inhibition; IFN-gamma reverses this inhibition to promote the appearance of the DR antigen, In contr ast, potentiation by T-4 of induction of HLA-DR by IFN-gamma requires activation of PKC, PKA is involved both in DR induction by IFN-gamma a nd in potentiation of the latter by T-4. Thus, PKA and PKC have discre te roles in IFN-gamma-induced MHC class II antigen expression and its modulation by thyroid hormone.