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

转录因子 NF-kB 和甲状腺激素受体之间的功能串扰

• 批准号: 12671078
• 负责人: NAGAYA Takashi
• 金额: $ 2.43万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671078/
• 关键词: Thyroid hormone receptor; NF-kB; euthyroid sick syndrome; Cytokine; Thyroid hormone; NF-кB; 甲状腺ホルモン受容体; TNFα; 悪液質; 組換えアデノウイルス

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.

为了阐明tnfa诱导的NF-kB对甲状腺激素作用的影响，我们将研究重点放在了甲状腺激素靶器官之一的肝脏上。使用人肝母细胞瘤驱动的HepG2细胞，我们在Northern blot分析中发现，在TNFa存在的情况下，T3对5‘脱碘酶（5’DI） mRNA表达的增加被减弱。在使用5'-DI启动子荧光素酶报告基因转染的实验中，T3对5'-DI Luc活性的诱导作用随着TNFa的处理而减弱，与Northern blot分析结果一致。为了研究TNFa的这种抑制作用是否由于活化的NF-kB，我们使用显性阴性NF-kB（p65 DN）作为工具。通过引入p65 DN，可阻止TNFa对t3依赖性的5’-DI mRNA或Luc活性升高的抑制作用，提示其抑制作用是通过NF-kB介导的。在脓毒症等严重情况下观察到的甲状腺功能亢进综合征中，循环TNFa升高、tnf - kb诱导的肝脏5′DI活性降低可能参与了甲状腺功能亢进综合征的发病机制。

项目成果

Nagaya T, 他: "A Potential role of activated NF-кB in the pathogenesis of euthyroid sick syndrome"J. Clin. Invest.. 106. 393-402 (2000)

Nagaya T 等人：“激活的 NF-кB 在甲状腺功能正常病态综合征发病机制中的潜在作用”J. Clin. 106. 393-402 (2000)

Kikumori T, 他: "Thyrotropin modifies activation of nuclear factor-κB by tumor necrosis factor α in rat thyroid cell line"Biochem. J.. 354. 573-579 (2000)

Kikumori T 等人：“促甲状腺素通过肿瘤坏死因子 α 在大鼠甲状腺细胞系中调节核因子-κB 的激活”Biochem J. 354. 573-579 (2000)

Sarkar D, 他: "Culture in vector-averaged gravity under clinostat rotation results in apoptosis of osteoblastic ROS 17/2.8 cells"J. Bone Miner. Res.. 15. 489-498 (2000)

Sarkar D 等人：“回转器旋转下的矢量平均重力培养导致成骨细胞 ROS 17/2.8 细胞凋亡”J. Bone Miner。15. 489-498 (2000)

Nagaya T, 他: "A Potential role of activated NF-κB in the pathogenesis of euthyroid sick syndrome"J. Clin. Invest.. 106. 393-402 (2000)

Nagaya T 等人：“活化的 NF-κB 在甲状腺功能正常病态综合征发病机制中的潜在作用”J. Clin. 106. 393-402 (2000)

長屋 敬, 他: "レチノイドX受容体(RXR)の蛋白分解による甲状腺ホルモン作用の修飾"ホルモンと臨床. 48. 31-39 (2000)

Takashi Nagaya 等人：“通过类视黄醇 X 受体 (RXR) 的蛋白水解作用来改变甲状腺激素的作用”《激素与临床科学》48. 31-39 (2000)。