Lin H Y, Thacore H R, Davis F B, Martino L J, Davis P J
Department of Medicine, Albany Medical College, NY 12208, USA.
J Interferon Cytokine Res. 1996 Jan;16(1):17-24. doi: 10.1089/jir.1996.16.17.
L-Thyroxine (T4) and 3,3',5-L-triiodothyronine (T3) potentiate the antiviral state induced by interferon-gamma(IFN-gamma) in homologous cells by a mechanism that is dependent upon calcium/phospholipid-dependent protein kinase (PKC). L-T4 and T3 also potentiate induction by IFN-gamma of MHC class II HLA-DR antigen expression in HeLa cells. In the present studies of HLA-DR expression, the PKC inhibitor staurosporine (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 IFN-gamma and 10(-7) M T4, the same concentrations of staurosporine inhibited potentiation of HLA-DR expression by thyroid hormone. A more specific PKC inhibitor, CGP41251 (0.5-5 nM), similarly enhanced HLA-DR expression in the presence of IFN-gamma but inhibited thyroid hormone potentiation of antigen expression. Both actions of CGP41251 were suppressed when cells were also treated with phorbol 12-myristate 13-acetate (PMA). A phospholipase C inhibitor, U73122 (1-1000 nM), did not alter the potentiating ability of T4, although it inhibited in a concentration-dependent manner the expression of HLA-DR induced by IFN-gamma. The potentiating effect of T4 was much more sensitive to a cyclic AMP-dependent protein kinase (PKA) inhibitor,KT5720 (1-1000nM), than was the induction of HLA-DR by IFN-gamma. The inhibitory effects of KT5720 were reversed by concurrent 8-bromo-cAMP treatment. The calmodulin antagonist W-7 (5-50 microM) did not alter IFN-gamma induction of HLA-DR in either the presence or absence of T4. HLA-DR expression in HeLa cells appears to be under PKC-associated inhibition; IFN-gamma reverses this inhibition to promote the appearance of the DR antigen. In contrast, potentiation by T4 of induction of HLA-DR by IFN-gamma requires activation of PKC. PKA is involved both in DR induction by IFN-gamma and in potentiation of the latter by T4. Thus, PKA and PKC have discrete roles in IFN-gamma-induced MHC class II antigen expression and its modulation by thyroid hormone.
L-甲状腺素（T4）和3,3',5-L-三碘甲状腺原氨酸（T3）通过一种依赖于钙/磷脂依赖性蛋白激酶（PKC）的机制，增强同源细胞中由γ干扰素（IFN-γ）诱导的抗病毒状态。L-T4和T3还能增强IFN-γ对HeLa细胞中MHC II类HLA-DR抗原表达的诱导作用。在目前关于HLA-DR表达的研究中，当PKC抑制剂星形孢菌素（0.1 - 1 nM）与100 IU/ml的IFN-γ同时添加时，可增强HLA-DR的表达。在IFN-γ和10⁻⁷ M T4存在的情况下，相同浓度的星形孢菌素会抑制甲状腺激素对HLA-DR表达的增强作用。一种更具特异性的PKC抑制剂CGP41251（0.5 - 5 nM），在IFN-γ存在时同样能增强HLA-DR的表达，但会抑制甲状腺激素对抗原表达的增强作用。当细胞同时用佛波醇12 - 肉豆蔻酸酯13 - 乙酸酯（PMA）处理时，CGP41251的这两种作用均被抑制。磷脂酶C抑制剂U73122（1 - 1000 nM）虽然以浓度依赖性方式抑制IFN-γ诱导的HLA-DR表达，但并未改变T4的增强能力。与IFN-γ诱导HLA-DR相比，T4的增强作用对环磷酸腺苷依赖性蛋白激酶（PKA）抑制剂KT5720（1 - 1000 nM）更为敏感。同时进行8 - 溴 - 环磷酸腺苷处理可逆转KT5720的抑制作用。无论有无T4，钙调蛋白拮抗剂W - 7（5 - 50 μM）均不改变IFN-γ对HLA-DR的诱导作用。HeLa细胞中的HLA-DR表达似乎受到与PKC相关的抑制；IFN-γ可逆转这种抑制作用以促进DR抗原的出现。相比之下，T4对IFN-γ诱导HLA-DR的增强作用需要激活PKC。PKA既参与IFN-γ诱导DR的过程，也参与T4对其的增强作用。因此，PKA和PKC在IFN-γ诱导的MHC II类抗原表达及其受甲状腺激素调节的过程中具有不同的作用。
