title: Estrogen-induced expression of tumor necrosis factor-like weak inducer of apoptosis through ERα accelerates the progression of lupus nephritis.
abstract: Oestrogens have been shown to play key roles in the pathogenesis of SLE. The aim of this study was to investigate the roles and mechanisms of 17β-estradiol (E2) in TNF-like weak inducer of apoptosis (TWEAK) expression in LN.
  
  
  
  Peripheral blood mononuclear cells (PBMCs) obtained from LN patients were used for in vitro experiments, while female MRL/lpr and MRL/MpJ mice were used for in vivo studies. E2, ICI 182 780 [estrogen receptor (ER)-selective antagonist], methyl-piperidino-pyrazole (MPP, ERα-selective modulator), lentivirus (LV)-TWEAK-short hairpin RNA (shRNA) and LV-control-shRNA treatments were used in this study.
  
  
  
  TWEAK mRNA expression in PBMCs was significantly increased following E2 treatment and downregulated after incubation with ICI 182 780 or MPP. Compared with sham-operated MRL/lpr mice, ovariectomized mice, treated with dimethyl sulphoxide vehicle alone, showed lower expression levels of renal TWEAK mRNA and protein. The expression of both mRNA and protein in ovariectomized mice was upregulated after E2 treatment and downregulated after ICI 182 780 or MPP co-treatment. Severe renal damage was observed in E2-treated ovariectomized mice, as were higher serum levels of IL-6, compared with dimethyl sulphoxide vehicle-treated ovariectomized mice. Co-treatment with LV-TWEAK-shRNA reversed these changes, and LV-control-shRNA treatment had no effect on them.
  
  
  
  Our results demonstrated that E2 plays an important role in the upregulation of TWEAK expression in LN, most likely through an ERα-dependent pathway, causing kidney damage. This provides a novel insight into the mechanisms of the E2-TWEAK signalling pathway in LN.
authors.affiliation: Department of Rheumatology and Immunology, the Second Affiliated Hospital of Soochow University, Suzhou.
authors.forename: Leixi
authors.initials: L
authors.lastname: Xue
authors.affiliation: Department of Biological Science & Engineering, Hebei University of Science & Technology, Hebei, China lzchun5190@sina.com.
authors.forename: Zhiqin
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Rheumatology and Immunology, the Second Affiliated Hospital of Soochow University, Suzhou.
authors.forename: Ji
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Rheumatology and Immunology, the Second Affiliated Hospital of Soochow University, Suzhou.
authors.forename: Jun
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Rheumatology and Immunology, the Second Affiliated Hospital of Soochow University, Suzhou.
authors.forename: Jian
authors.initials: J
authors.lastname: Wen
authors.affiliation: Department of Rheumatology and Immunology, the Second Affiliated Hospital of Soochow University, Suzhou.
authors.forename: Zhichun
authors.initials: Z
authors.lastname: Liu
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology; D000293:Adolescent; D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D000074049:Cytokine TWEAK; D015536:Down-Regulation; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000502:physiology; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008181:Lupus Nephritis / Q000209:etiology*; D051379:Mice; D008875:Middle Aged; D010053:Ovary / Q000601:surgery; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D048069:Tumor Necrosis Factors / Q000494:pharmacology / Q000502:physiology*; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D000074049:Cytokine TWEAK; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D012333:RNA, Messenger; C109743:TNFSF12 protein, human; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors; D004958:Estradiol
keywords: 17β-estradiol (E2); estrogen receptor alpha (ERα); systemic lupus erythematosus (SLE); tumor necrosis factor–like weak inducer of apoptosis (TWEAK)