Estrogen Receptor [alpha] Regulates Tripartite Motif-Containing Protein 21 Expression, Contributing to Dysregulated Cytokine Production in Systemic Lupus Erythematosus

Objective To examine the role of 17[beta]-estradiol in the regulation of the autoantigen tripartite motif-containing protein 21 (TRIM-21) in patients with systemic lupus erythematosus (SLE). Methods Monocytes isolated from healthy control subjects and patients with SLE were stimulated with 17[beta]-estradiol and/or the estrogen receptor [alpha] (ER[alpha]) antagonist methyl-piperidino-pyrazole dihydrochloride. TRIM-21, ER[alpha], and CREM[alpha] expression was determined by real-time polymerase chain reaction (PCR) analysis. MatInspector software was used to identify putative binding sites within the TRIM-21 promoter. ER[alpha] binding to the TRIM-21 gene promoter region in monocytes was analyzed by chromatin immunoprecipitation (ChIP) assay. TRIM-21 and interferon regulatory factor 3 protein levels were analyzed by Western blotting. Results Real-time PCR analysis demonstrated a role of estrogen in the regulation of TRIM-21 expression in monocytes, which correlated positively with ER[alpha] gene expression in patients with SLE. Investigations into the human TRIM-21 promoter revealed the presence of an estrogen response element, with ChIP assays confirming ER[alpha] binding to this site. Studies into estrogen-induced TRIM-21 expression revealed a hyperresponsiveness of SLE patients to 17[beta]-estradiol, which led to the enhanced levels of TRIM-21 observed in these individuals. Conclusion Our results demonstrate a role of estrogen in the regulation of TRIM-21 expression through an ER[alpha]-dependent mechanism, a pathway that we observed to be overactive in SLE patients. Treatment of monocytes with an ER[alpha] antagonist abrogated estrogen-induced TRIM-21 expression and, as a consequence, decreased the expression of interleukin-23. These findings identify TRIM-21 as a novel ER[alpha]-regulated gene and provide novel insights into the link between estrogen and the molecular pathogenesis of SLE.