Copyright © 2006, European Society of Cardiology
Estradiol blocks the induction of CD40 and CD40L expression on endothelial cells and prevents neutrophil adhesion: An ER
-mediated pathway
aResearch Center of Montreal Heart Institute, Université de Montréal, Montréal, Québec, Canada
bDepartment of Medicine of Montreal Heart Institute, Université de Montréal, Montréal, Québec, Canada
cDepartment of Pharmacology, Université de Montréal, Montréal, Québec, Canada
* Corresponding author. Research Center, Montreal Heart Institute, 5000 Belanger Street, Montréal, Québec, Canada H1T 1C8. Tel.: +1 514 376 3330x3250; fax: +1 514 593 2596. Email address: pascale.geoffroy{at}icm-mhi.org
Objective: Interferon gamma (IFN-
) was shown to induce CD40 and CD40L expression on endothelial cells (ECs) and consequently to promote neutrophil adhesion. The pro- and anti-inflammatory effects of estrogens are well recognized but their role on the regulation of CD40 and CD40L expression on ECs remains undefined.
Methods and results Treatment of porcine aortic endothelial cells (PAEC) with IFN- for 24 h enhanced CD40 and CD40L expression by 97% and 78%, respectively. Pretreatment of PAEC with 17-beta-estradiol (17βE) for 24 h prevented the latter expression of CD40/CD40L. Treatment of PAEC with antisense oligomers targeting ER
mRNA attenuated the ability of 17βE to inhibit the IFN--induced CD40 and CD40L protein expression. The IFN- activation pathway of CD40 is known to involve the phosphorylation of the Janus activated kinase (JAK) and the signal transducer and activator of transcription 1 (Stat1). 17βE, acting via the estrogen receptor (ER), abrogated IFN--mediated effects on Stat1 but failed to inhibit Jak1 and Jak2 phosphorylation. Furthermore, 17βE prevented neutrophil adhesion induced by IFN-.
Conlusion In summary, 17βE binding to ER blocked IFN--induced Stat1 phosphorylation, CD40 and CD40L protein expression, and neutrophil adhesion onto ECs.
KEYWORDS Restenosis; Estrogens; Cytokines; Receptors; Endothelial function
Time for primary review 20 days
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