Estrogen-induced expression of tumor necrosis factor-like weak inducer of apoptosis through ERα accelerates the progression of lupus nephritis

Objectives. 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 17 beta-estradiol (E2) in TNF-like weak inducer of apoptosis (TWEAK) expression in LN. Methods. 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, ER alpha-selective modulator), lentivirus (LV)-TWEAK-short hairpin RNA (shRNA) and LV-control-shRNA treatments were used in this study. Results. 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. Conclusion. Our results demonstrated that E2 plays an important role in the upregulation of TWEAK expression in LN, most likely through an ER alpha-dependent pathway, causing kidney damage. This provides a novel insight into the mechanisms of the E2-TWEAK signalling pathway in LN.