Functional crosstalk between transcription factor NF-kB and thyroid hormone receptor

为了阐明TNFa诱导的核因子-kB对甲状腺激素作用的影响，我们重点研究了作为甲状腺激素靶器官之一的肝脏。利用人肝母细胞瘤驱动的HepG2细胞，我们在Northern印迹分析中证明，在TNFa存在的情况下，T3对5‘脱碘酶(5’DI)mRNA表达的增加是恶化的。在5‘-DI启动子荧光素酶报告基因的转染实验中，经TNFa处理后，T3对5’-DI Luc活性的诱导作用减弱，这与Northern印迹分析结果一致。为了研究TNFa的这种抑制作用是否是由于激活了核因子-kB，我们使用了显性负核因子-kB(P65dN)作为工具。通过引入p65 dN，可阻止TNFa抑制T_3依赖性5‘-DI mRNA或Luc活性的增加，提示这种抑制作用是通过核因子-kB介导的。在严重的脓毒症等情况下观察到的正常甲状腺灯芯综合征，循环中的TNFa升高和肝脏5‘DI活性降低可能参与了正常甲状腺疾病综合征的发病过程。

To elucidate the effect of TNFa-induced NF-kB on thyroid hormone action, we focused the studies on liver that is one of the target organs of thyroid hormone.Using human hepatoblastoma-drived HepG2 cells, we demonstrated that an increase of 5'deiodinase(5'DI) mRNA expression by T3 was deteriorated in the presence of TNFa in Northern blot analysis. In transfection assays using 5'-DI promoter luciferase reporter gene, the induction of 5'-DI Luc activity by T3 was reduced with the treatment of TNFa, in concordance with the results of Northern blot analysis. To study whether this inhibitory effect of TNFa is due to activated NF-kB, we used dominant negative NF-kB(p65 DN) as a tool. The inhibition of T3-dependent increase of 5'-DI mRNA or Luc activity by TNFa was prevented by introducing p65 DN, suggesting that the inhibitory effect was mediated through NF-kB. In euthyroid wick syndrome observed in severe conditions of sepsis, etc., elevated circulating TNFa and decreased hepatic 5' DI activity by TNFa-induced NF-kB would be involved in the pathogenesis of euthyroid sick syndrome.