Estrogen Receptor α Regulates Tripartite Motif–Containing Protein 21 Expression, Contributing to Dysregulated Cytokine Production in Systemic Lupus Erythematosus

• Published in: Arthritis & rheumatology (Hoboken, N.J.) Vol. 66; no. 1; pp. 163 - 172
• Main 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.
• Format: Journal Article
• Language: English
• Published: United States 01.01.2014
• Subjects: Adult; Autoantigens; Case-Control Studies; Cells, Cultured; Chromatin Immunoprecipitation; Cyclic AMP Response Element Modulator - genetics; Cyclic AMP Response Element Modulator - metabolism; Cytokines - biosynthesis; Estradiol - physiology; Estrogen Receptor alpha - antagonists & inhibitors; Estrogen Receptor alpha - metabolism; Female; Gene Expression Regulation; Humans; Lupus Erythematosus, Systemic - metabolism; Male; Middle Aged; Monocytes - metabolism; Promoter Regions, Genetic; Real-Time Polymerase Chain Reaction; Response Elements - physiology; Ribonucleoproteins - genetics; Ribonucleoproteins - metabolism; Young Adult
• DOI: 10.1002/art.38187
• ISSN: 2326-5191; 2326-5205

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.