Background/Purpose: Systemic lupus erythematosus (SLE) disproportionally affects females (9:1) over males. Despite significant research effort, the exact mechanisms behind this compelling sex bias are undefined. Our prior studies demonstrate a significant role for estrogen receptor alpha (ERα) mediated inflammation in the pathogenesis of disease. NZM2410 lupus prone mice, expressing a truncated ERα functional knockout, survived longer and had significantly reduced renal disease. Yet, a complete knockout of ERα was not protective, suggesting the truncated isoform may be protective with the full-length gene necessary for disease.

Methods: Our goal is to identify the molecular mechanisms utilized by liganded ERα in regulating the inflammatory milieu. To understand ERα function, transient transfections of full length ERα and a shortened isoform ERα46 (lacking the AF-1 activation domain and similar to the functional knockout) were performed in MDA-MB-231 cells, which lack ERα and mRNA of inflammatory cytokines and cellular proliferation markers examined. Additionally, we identified ERα associated target genes and determined differences in their expression in B cells isolated from female African American (AA) lupus patients with an average age of 45.5 years and matched healthy controls.

Results: Transfection results indicate that both ERα46 reduces ERα66 driven mRNA expression of IL-1β one hour after stimulation with a TLR4 agonist. Similar results were also obtained for the cellular proliferation and survival markers MAPK14 and KLF4. Interestingly, an additive increase in expression was seen for TFF1, another cellular proliferation marker one hour after stimulation. RNA-seq analysis indicates that 60% of ERα associated target genes were differentially expressed between patients and controls. The majority of these genes (82%) were upregulated in lupus patients compared to controls. Genes with increased expression were included TLRs, NFκB related transcription factors and IL-1β.

Conclusion: These results further support a role for ERα in the pathogenesis of SLE. Future goals include utilizing high throughput sequencing technology to examine the transcriptional impact of liganded ERα in B cells of African American pediatric lupus patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/examining-the-transcriptional-impact-of-liganded-er%ce%b1-in-the-inflammatory-milieu-of-systemic-lupus-erythematosus/