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- Title
Estrogen Receptor α Regulates Tripartite Motif-Containing Protein 21 Expression, Contributing to Dysregulated Cytokine Production in Systemic Lupus Erythematosus.
- Authors
Smith, Siobhán; Ní Gabhann, Joan; McCarthy, Eoghan; Coffey, Barbara; Mahony, Rebecca; Byrne, Jennifer C.; Stacey, Kevin; Ball, Elizabeth; Bell, Aubrey; Cunnane, Gaye; Doran, Michele F.; Molloy, Eamonn S.; Lee, Ruth Z.; Harvey, Brian; Kearns, Grainne; Jefferies, Caroline A.
- Abstract
Objective To examine the role of 17β-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 17β-estradiol and/or the estrogen receptor α (ERα) antagonist methyl-piperidino-pyrazole dihydrochloride. TRIM-21, ERα, and CREMα 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. ERα 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 ERα 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 ERα binding to this site. Studies into estrogen-induced TRIM-21 expression revealed a hyperresponsiveness of SLE patients to 17β-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 ERα-dependent mechanism, a pathway that we observed to be overactive in SLE patients. Treatment of monocytes with an ERα 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 ERα-regulated gene and provide novel insights into the link between estrogen and the molecular pathogenesis of SLE.
- Publication
Arthritis & Rheumatology, 2014, Vol 66, Issue 1, p163
- ISSN
2326-5191
- Publication type
Journal Article
- DOI
10.1002/art.38187