Bo Qu1, Jianchang Cao2, Feifei Zhang2, Huijuan Cui3, Jialin Teng3, Jia Li3, Zheng Liu4, Chris Morehouse4, Bahija Jallal4, Yuanjia Tang3, Qiang Guo3, Yihong Yao4, Nan Shen5. 1. 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. 2. Institute of Health Sciences of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Shanghai Jiao Tong University School of Medicine, Shanghai, China. 3. Renji Hospital and Shanghai Jiao Tong University School of Medicine, Shanghai, China. 4. MedImmune, Gaithersburg, Maryland. 5. 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, and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
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.
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 SLEpatients 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.
Authors: Ha Won Lee; Samia Q Khan; Shehryar Khaliqdina; Mehmet M Altintas; Florian Grahammer; Jimmy L Zhao; Kwi Hye Koh; Nicholas J Tardi; Mohd Hafeez Faridi; Terese Geraghty; David J Cimbaluk; Katalin Susztak; Luis F Moita; David Baltimore; Pierre-Louis Tharaux; Tobias B Huber; Matthias Kretzler; Markus Bitzer; Jochen Reiser; Vineet Gupta Journal: J Biol Chem Date: 2016-12-02 Impact factor: 5.157