Estradiol blocks the induction of CD40 and CD40L expression on endothelial cells and prevents neutrophil adhesion: An ER{alpha}-mediated pathway

doi:10.1016/j.cardiores.2006.05.015

Cardiovascular Research 2006 71(3):566-573; doi:10.1016/j.cardiores.2006.05.015

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Estradiol blocks the induction of CD40 and CD40L expression on endothelial cells and prevents neutrophil adhesion: An ER ${alpha}$ -mediated pathway

Pedro Geraldes^a^,b, Stéphanie Gagnon^a^,b, Sofiane Hadjadj^a, Yahye Merhi^a^,b, Martin G. Sirois^a^,c, Isabelle Cloutier^a and Jean-François Tanguay^a^,b^,*

^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- ${gamma}$ ) was shown to induce CD40and CD40L expression on endothelial cells (ECs) and consequentlyto promote neutrophil adhesion. The pro- and anti-inflammatoryeffects of estrogens are well recognized but their role on theregulation of CD40 and CD40L expression on ECs remains undefined.

Methods and results Treatment of porcine aortic endothelialcells (PAEC) with IFN- ${gamma}$ for 24 h enhanced CD40 and CD40Lexpression by 97% and 78%, respectively. Pretreatment of PAECwith 17-beta-estradiol (17βE) for 24 h prevented thelatter expression of CD40/CD40L. Treatment of PAEC with antisenseoligomers targeting ER ${alpha}$ mRNA attenuated the ability of 17βEto inhibit the IFN- ${gamma}$ -induced CD40 and CD40L protein expression.The IFN- ${gamma}$ activation pathway of CD40 is known to involve thephosphorylation of the Janus activated kinase (JAK) and thesignal transducer and activator of transcription 1 (Stat1).17βE, acting via the estrogen receptor ${alpha}$ (ER ${alpha}$ ), abrogatedIFN- ${gamma}$ -mediated effects on Stat1 but failed to inhibit Jak1 andJak2 phosphorylation. Furthermore, 17βE prevented neutrophiladhesion induced by IFN- ${gamma}$ .

Conlusion In summary, 17βE binding to ER ${alpha}$ blocked IFN- ${gamma}$ -inducedStat1 phosphorylation, CD40 and CD40L protein expression, andneutrophil adhesion onto ECs.

KEYWORDS Restenosis; Estrogens; Cytokines; Receptors; Endothelial function

Time for primary review 20 days

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Cardiovascular Research

Estradiol blocks the induction of CD40 and CD40L expression on endothelial cells and prevents neutrophil adhesion: An ER-mediated pathway

Estradiol blocks the induction of CD40 and CD40L expression on endothelial cells and prevents neutrophil adhesion: An ER ${alpha}$ -mediated pathway