Estrogen receptor α 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 beta-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.