Premium
Estrogen Receptor α Regulates Tripartite Motif–Containing Protein 21 Expression, Contributing to Dysregulated Cytokine Production in Systemic Lupus Erythematosus
Author(s) -
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.
Publication year - 2014
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.38187
Subject(s) - estrogen , trim , chromatin immunoprecipitation , estrogen receptor , endocrinology , medicine , gene expression , biology , promoter , gene , genetics , cancer , breast cancer , computer science , operating system
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.