title: MicroRNA-146A contributes to abnormal activation of the type I interferon pathway in human lupus by targeting the key signaling proteins.
abstract: OBJECTIVE
  MicroRNA have recently been identified as regulators that modulate target gene expression and are involved in shaping the immune response. This study was undertaken to investigate the contribution of microRNA-146a (miR-146a), which was identified in the pilot expression profiling step, to the pathogenesis of systemic lupus erythematosus (SLE).
  
  
  METHODS
  TaqMan microRNA assays of peripheral blood leukocytes were used for comparison of expression levels of microRNA between SLE patients and controls. Transfection and stimulation of cultured cells were conducted to determine the biologic function of miR-146a. Bioinformatics prediction and validation by reporter gene assay and Western blotting were performed to identify miR-146a targets.
  
  
  RESULTS
  Profiling of 156 miRNA in SLE patients revealed the differential expression of multiple microRNA, including miR-146a, a negative regulator of innate immunity. Further analysis showed that underexpression of miR-146a negatively correlated with clinical disease activity and with interferon (IFN) scores in patients with SLE. Of note, overexpression of miR-146a reduced, while inhibition of endogenous miR-146a increased, the induction of type I IFNs in peripheral blood mononuclear cells (PBMCs). Furthermore, miR-146a directly repressed the transactivation downstream of type I IFN. At the molecular level, miR-146a could target IFN regulatory factor 5 and STAT-1. More importantly, introduction of miR-146a into the patients' PBMCs alleviated the coordinate activation of the type I IFN pathway.
  
  
  CONCLUSIONS
  The microRNA miR-146a is a negative regulator of the IFN pathway. Underexpression of miR-146a contributes to alterations in the type I IFN pathway in lupus patients by targeting the key signaling proteins. The findings provide potential novel strategies for therapeutic intervention.
authors.affiliation: Joint Molecular Rheumatology Laboratory of the Institute of Health Sciences and Shanghai Renji Hospital, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Yuanjia
authors.initials: Y
authors.lastname: Tang
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Luo
authors.forename: Huijuan
authors.initials: H
authors.lastname: Cui
authors.forename: Xuming
authors.initials: X
authors.lastname: Ni
authors.forename: Min
authors.initials: M
authors.lastname: Yuan
authors.forename: Yanzhi
authors.initials: Y
authors.lastname: Guo
authors.forename: Xinfang
authors.initials: X
authors.lastname: Huang
authors.forename: Haibo
authors.initials: H
authors.lastname: Zhou
authors.forename: Niek
authors.initials: N
authors.lastname: de Vries
authors.forename: Paul Peter
authors.initials: PP
authors.lastname: Tak
authors.forename: Shunle
authors.initials: S
authors.lastname: Chen
authors.forename: Nan
authors.initials: N
authors.lastname: Shen