title: New insights into the role and mechanism of macrophage migration inhibitory factor in steroid-resistant patients with systemic lupus erythematosus.
abstract: BACKGROUND
  Glucocorticoid (GC) therapy remains important in improving the prognosis of patients with systemic lupus erythematosus (SLE). However, some patients do not achieve an effective response with GC treatment, creating an obstacle to the remission of SLE. Identification of the underlying mechanisms responsible for steroid resistance can be significant. Macrophage migration inhibitory factor (MIF) arouses our interest because of its reciprocal relationship with GCs. In the present study, we investigated for the first time whether MIF correlated with steroid resistance in SLE and explored potential mechanisms of action.
  
  
  METHODS
  Sixty-two patients with SLE (40 steroid sensitive and 22 steroid resistant) and 21 normal controls were recruited. Serum levels of MIF were measured by ELISA. Cytosolic MIF and IκB expression in peripheral blood mononuclear cells (PBMCs) were determined by western blotting. The electrophoretic mobility shift assay was assessed by NF-κB in nuclear aliquots. Gene silencing was applied to reduce expression of MIF in PBMCs in steroid-resistant patients. PBMCs obtained from steroid-sensitive patients were treated with recombinant human MIF of different concentrations.
  
  
  RESULTS
  MIF levels in serum and PBMCs were higher in steroid-resistant patients compared with steroid-sensitive patients and controls. In contrast to the steroid-sensitive group, NF-κB levels were significantly higher and IκB levels lower in steroid-resistant patients. After MIF gene silencing, IκB levels in cells from steroid-resistant patients were increased. In steroid-sensitive patients, a decrease in IκB levels and an increase in NF-κB expression from baseline were detected in PBMCs treated with a higher concentration of recombinant human MIF. Treatment with recombinant human MIF did not regulate expression of IκB and NF-κB in PBMCs from patients treated with an anti-MIF monoclonal antibody.
  
  
  CONCLUSIONS
  Our results indicated that MIF may play a role in the formation of steroid resistance in SLE by affecting the NF-κB/IκB signaling cascade. As a regulator of glucocorticoid sensitivity, MIF may be a potential target for steroid sparing.
authors.affiliation: Department of Rheumatology, Renji Hospital, Shanghai Jiaotong University School of Medicine, 145 Middle Shan Dong Road, Shanghai 200001, China.
authors.forename: Fang-Fang
authors.initials: FF
authors.lastname: Wang
authors.forename: Li-An
authors.initials: LA
authors.lastname: Zhu
authors.forename: Yu-Qiong
authors.initials: YQ
authors.lastname: Zou
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.forename: Alisa
authors.initials: A
authors.lastname: Wilson
authors.forename: Cheng-De
authors.initials: CD
authors.lastname: Yang
authors.forename: Nan
authors.initials: N
authors.lastname: Shen
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wallace
authors.forename: Michael H
authors.initials: MH
authors.lastname: Weisman
authors.forename: Shun-Le
authors.initials: SL
authors.lastname: Chen
authors.forename: Liang-Jing
authors.initials: LJ
authors.lastname: Lu
mesh_terms: D000328:Adult; D015153:Blotting, Western; D004351:Drug Resistance / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000032:analysis / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000032:analysis / Q000378:metabolism*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection
chemical_list: D005938:Glucocorticoids; D008263:Macrophage Migration-Inhibitory Factors; D016328:NF-kappa B; D034741:RNA, Small Interfering; D051550:I-kappa B Kinase; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human