title: Type I Interferon Inhibition of MicroRNA-146a Maturation Through Up-Regulation of Monocyte Chemotactic Protein-Induced Protein 1 in Systemic Lupus Erythematosus.
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.
  
  
  CONCLUSIONS
  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: 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.
authors: Bo
authors: B
authors: Qu
authors: Institute of Health Sciences of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Jianchang
authors: J
authors: Cao
authors: Institute of Health Sciences of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Feifei
authors: F
authors: Zhang
authors: Renji Hospital and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Huijuan
authors: H
authors: Cui
authors: Renji Hospital and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Jialin
authors: J
authors: Teng
authors: Renji Hospital and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Jia
authors: J
authors: Li
authors: MedImmune, Gaithersburg, Maryland.
authors: Zheng
authors: Z
authors: Liu
authors: MedImmune, Gaithersburg, Maryland.
authors: Chris
authors: C
authors: Morehouse
authors: MedImmune, Gaithersburg, Maryland.
authors: Bahija
authors: B
authors: Jallal
authors: Renji Hospital and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Yuanjia
authors: Y
authors: Tang
authors: Renji Hospital and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Qiang
authors: Q
authors: Guo
authors: MedImmune, Gaithersburg, Maryland.
authors: Yihong
authors: Y
authors: Yao
authors: 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.
authors: Nan
authors: N
authors: Shen
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics / Q000276:immunology; D000954:Antigens, Surface / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D058851:GPI-Linked Proteins / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D007962:Leukocytes / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D035683:MicroRNAs / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D064547:Myxovirus Resistance Proteins / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012260:Ribonucleases / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D014157:Transcription Factors / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000954:Antigens, Surface; D058851:GPI-Linked Proteins; D007370:Interferon Type I; C439870:LY6E protein, human; D008070:Lipopolysaccharides; C542542:MIRN146 microRNA, human; C579071:MX1 protein, human; D035683:MicroRNAs; D064547:Myxovirus Resistance Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; C475085:OAS1 protein, human; D015088:2',5'-Oligoadenylate Synthetase; D012260:Ribonucleases; C510646:ZC3H12A protein, human