17b-Estradiol Potentiates the Type I Interferon Signature and Pro-inflammatory Cytokine Profile in SLE via ERa Signaling 2309771

Abstract Introduction Systemic Lupus Erythematosus (SLE) is a life-threatening autoimmune disease with a profound female predominance, yet the molecular nexus between sex hormones and inflammatory pathways remains poorly defined. This study aims to identify and validate E2-responsive candidate genes and signaling networks that drive SLE pathogenesis. Methods Peripheral blood mononuclear cells (PBMCs) from SLE patients (n = 3) and healthy controls (n = 3) were treated in vitro with physiological concentrations of 17b-estradiol. We utilized Gene-chip transcriptomic analysis to identify differentially expressed genes (DEGs). Cytokine profiles (IL-6, IL-12, IL-17, IL-21) were quantified in patient plasma via ELISA and correlated with systemic E2 levels. T cell activation (CD69) and cytokine production (IFN-g) were assessed by flow cytometry. Results Plasma levels of pro-inflammatory cytokines (IL-6, IL-12, IL-17, and IL-21) were significantly elevated in SLE patients and positively correlated with endogenous E2 concentrations. In vitro E2 stimulation differentially upregulated pathways involved in G-protein coupled receptor (GPCR) signaling, apoptosis, and TNF/IFN-mediated inflammation. Notably, E2 treatment induced a 30-fold increase in IL-1 expression in SLE PBMCs compared to a 7-fold increase in healthy controls. Gene-chip analysis identified TNFAIP3 (A20) as a key E2-responsive ISG. Furthermore, E2 significantly increased the frequencies of activated CD3+CD69+ and IFNg+ T cells. These effects were abrogated by simultaneous ERa inhibition, establishing an ERa dependent mechanism for ISG and cytokine dysregulation. Conclusion Our findings demonstrate that 17b-estradiol acts as a potent rheostat for the IFN signature and pro-inflammatory milieu in SLE. The hyper-responsiveness of SLE PBMCs to E2-induced IL-1 and ISG expression provides a mechanistic basis for the sexual dimorphism observed in SLE. Targeting the E2-ERa signaling axis may represent a viable strategy for attenuating the inflammatory cascade in SLE patients. Funding Source This work was supported by the NIH grants AR54034, AI 083894,AI65645, I01 BX 005887-01 to RPS; UCLA Senate Core Grant to BHH and RPS; UCLA Oppenheimer Clinical Seed Grant and American Autoimmune Related Disease Association grant to RPS. Topic Categories Immune Mechanisms of Human Disease (HUM)