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吡咯烷二硫代氨基甲酸盐(PDTC)通过钙调神经磷酸酶活性调节因子1(RCAN1)的表达抑制炎症信号传导:PDTC通过诱导RCAN1的抗炎机制。

Pyrrolidine dithiocarbamate (PDTC) inhibits inflammatory signaling via expression of regulator of calcineurin activity 1 (RCAN1): Anti-inflammatory mechanism of PDTC through RCAN1 induction.

作者信息

Lee Eun Hye, Kim Seon Sook, Seo Su Ryeon

机构信息

Department of Molecular Bioscience, College of Biomedical Science, Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon 200-701, Republic of Korea.

Department of Molecular Bioscience, College of Biomedical Science, Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon 200-701, Republic of Korea.

出版信息

Biochem Pharmacol. 2017 Nov 1;143:107-117. doi: 10.1016/j.bcp.2017.07.011. Epub 2017 Jul 14.

Abstract

Pyrrolidine dithiocarbamate (PDTC) is a thiol compound that elicits anti-inflammatory effects by inhibiting NF-κB signaling. In this study, we report that regulator of calcineurin activity 1 (RCAN1) expression is induced by PDTC treatment and that increased RCAN1 expression is dependent on the generation of reactive oxygen species (ROS) and activation of p38 MAPK and JNK signaling. We also report that the ability of PDTC to induce RCAN1 is mediated by activator protein-1 (AP-1)-dependent gene transcription, and identified a functional AP-1 binding site in the RCAN1 promoter by producing mutations and conducting chromatin immunoprecipitation (ChIP) analyses. Moreover, we show that the PDTC-mediated inhibitory effect on NF-κB signaling is significantly perturbed by knocking out RCAN1. Our data provide the first evidence that PDTC prevents in vivo expression of pro-inflammatory cytokines by inducing RCAN1 expression.

摘要

吡咯烷二硫代氨基甲酸盐(PDTC)是一种硫醇化合物,可通过抑制核因子κB(NF-κB)信号传导发挥抗炎作用。在本研究中,我们报告称,PDTC处理可诱导钙调神经磷酸酶活性调节因子1(RCAN1)的表达,且RCAN1表达的增加依赖于活性氧(ROS)的产生以及p38丝裂原活化蛋白激酶(MAPK)和应激活化蛋白激酶(JNK)信号传导的激活。我们还报告称,PDTC诱导RCAN1的能力是由激活蛋白-1(AP-1)依赖的基因转录介导的,并通过产生突变和进行染色质免疫沉淀(ChIP)分析,在RCAN1启动子中鉴定出一个功能性AP-1结合位点。此外,我们表明,敲除RCAN1会显著干扰PDTC介导的对NF-κB信号传导的抑制作用。我们的数据首次证明,PDTC通过诱导RCAN1表达来阻止体内促炎细胞因子的表达。

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