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 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.


CONCLUSIONS
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.
Royal College of Surgeons in Ireland, Dublin, Ireland.
Siobhán
S
Smith
Joan
J
Ní Gabhann
Eoghan
E
McCarthy
Barbara
B
Coffey
Rebecca
R
Mahony
Jennifer C
JC
Byrne
Kevin
K
Stacey
Elizabeth
E
Ball
Aubrey
A
Bell
Gaye
G
Cunnane
Michele F
MF
Doran
Eamonn S
ES
Molloy
Ruth Z
RZ
Lee
Brian
B
Harvey
Grainne
G
Kearns
Caroline A
CA
Jefferies
D000328:Adult; D001324:Autoantigens; D016022:Case-Control Studies; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D051786:Cyclic AMP Response Element Modulator / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis*; D004958:Estradiol / Q000502:physiology*; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D060888:Real-Time Polymerase Chain Reaction; D020218:Response Elements / Q000502:physiology*; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult; D000099207:SS-A Antigen
D001324:Autoantigens; D051786:Cyclic AMP Response Element Modulator; D016207:Cytokines; D004958:Estradiol; D047628:Estrogen Receptor alpha; D012261:Ribonucleoproteins; D000099207:SS-A Antigen; C497410:CREM protein, human