系统性红斑狼疮中 I 型干扰素通过上调单核细胞趋化蛋白诱导蛋白 1 抑制 microRNA-146a 成熟。

Type I Interferon Inhibition of MicroRNA-146a Maturation Through Up-Regulation of Monocyte Chemotactic Protein-Induced Protein 1 in Systemic Lupus Erythematosus.

机构信息

Renji Hospital, Shanghai Jiao Tong University School of Medicine, Institute of Health Sciences of Shanghai Institutes for Biological Sciences, and Chinese Academy of Sciences, Shanghai, China.

Institute of Health Sciences of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Shanghai Jiao Tong University School of Medicine, Shanghai, China.

出版信息

Arthritis Rheumatol. 2015 Dec;67(12):3209-18. doi: 10.1002/art.39398.

DOI:10.1002/art.39398

PMID:26315540

Abstract

OBJECTIVE

Systemic lupus erythematosus (SLE) is characterized by the uncontrolled production of inflammatory cytokines, among which type I interferon (IFN) is recognized as a crucial pathogenic factor. The expression of microRNA-146a (miR-146a) is reduced in the white blood cells of SLE patients and accounts for their overactivated inflammatory responses. However, the mechanism of the reduction of miR-146a is still not fully understood. This study was undertaken to test whether the key pathogenic cytokine, type I IFN, is responsible for the dysregulation of miR-146a in SLE.

METHODS

Gene and protein expression was measured in all cells by reverse transcription-quantitative polymerase chain reaction, Northern blotting, or Western blotting. In THP-1 cells, expression of monocyte chemotactic protein-induced protein 1 (MCPIP-1) was knocked down with a lentivirus encoding a short hairpin RNA targeting MCPIP1. The cells were pretreated with type I IFN and assessed for gene expression levels of miR-146a. White blood cells from patients with SLE were analyzed for the expression of the IFN-inducible genes MCPIP1 and miR-146a, and the gene expression data were compared for correlation.

RESULTS

Pretreatment of THP-1 cells with type I IFN attenuated the induction of miR-146a posttranscriptionally, by down-regulating the expression of pre-miR-146a but not pri-miR-146a or its original unspliced transcript. Expression of MCPIP-1, which was enhanced by type I IFN, was found to be responsible for the inhibition of miR-146a. In white blood cells from patients with SLE, MCPIP1 expression was elevated, and its expression correlated positively with the IFN score and negatively with the miR-146a transcript level.

CONCLUSION

Type I IFN inhibits the maturation of miR-146a through the up-regulation of MCPIP-1, and thus contributes to the uncontrolled inflammation and excessive inflammatory gene expression in SLE.

摘要

目的

系统性红斑狼疮（SLE）的特征是炎症细胞因子的不受控制的产生，其中 I 型干扰素（IFN）被认为是一个关键的致病因素。SLE 患者白细胞中的 microRNA-146a（miR-146a）表达降低，导致其过度激活的炎症反应。然而，miR-146a 减少的机制仍不完全清楚。本研究旨在检验关键致病细胞因子 I 型 IFN 是否导致 SLE 中 miR-146a 的失调。

方法

通过逆转录定量聚合酶链反应、Northern 印迹或 Western 印迹测量所有细胞中的基因和蛋白质表达。在 THP-1 细胞中，使用编码靶向 MCPIP1 的短发夹 RNA 的慢病毒敲低单核细胞趋化蛋白诱导蛋白 1（MCPIP-1）的表达。用 I 型 IFN 预处理细胞，并评估 miR-146a 的基因表达水平。分析 SLE 患者的白细胞中 IFN 诱导基因 MCPIP1 和 miR-146a 的表达，并对基因表达数据进行相关性分析。

结果

I 型 IFN 预处理 THP-1 细胞可通过下调前体 miR-146a 的表达而不是 pri-miR-146a 或其原始未剪接转录物来减弱 miR-146a 的诱导。发现 I 型 IFN 增强的 MCPIP-1 的表达负责抑制 miR-146a。在 SLE 患者的白细胞中，MCPIP1 的表达升高，其表达与 IFN 评分呈正相关，与 miR-146a 转录物水平呈负相关。