Estradiol blocks the induction of CD40 and CD40L expression on endothelial cells and prevents neutrophil adhesion: an ERalpha-mediated pathway.
OBJECTIVE
Interferon gamma (IFN-gamma) 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.


RESULTS
Treatment of porcine aortic endothelial cells (PAEC) with IFN-gamma for 24 h enhanced CD40 and CD40L expression by 97% and 78%, respectively. Pretreatment of PAEC with 17-beta-estradiol (17betaE) for 24 h prevented the latter expression of CD40/CD40L. Treatment of PAEC with antisense oligomers targeting ERalpha mRNA attenuated the ability of 17betaE to inhibit the IFN-gamma-induced CD40 and CD40L protein expression. The IFN-gamma 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). 17betaE, acting via the estrogen receptor alpha (ERalpha), abrogated IFN-gamma-mediated effects on Stat1 but failed to inhibit Jak1 and Jak2 phosphorylation. Furthermore, 17betaE prevented neutrophil adhesion induced by IFN-gamma.


CONCLUSIONS
In summary, 17betaE binding to ERalpha blocked IFN-gamma-induced Stat1 phosphorylation, CD40 and CD40L protein expression, and neutrophil adhesion onto ECs.
Geraldes
Pedro
P
Research Center of Montreal Heart Institute, Department of Medicine, Université de Montréal, Montréal, Québec, Canada.
Gagnon
Stéphanie
S
Hadjadj
Sofiane
S
Merhi
Yahye
Y
Sirois
Martin G
MG
Cloutier
Isabelle
I
Tanguay
Jean-François
JF
D000818:Animals; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism*; D023201:CD40 Ligand / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000502:physiology; D047629:Estrogen Receptor beta / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013552:Swine
D019013:CD40 Antigens; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D012333:RNA, Messenger; D011994:Recombinant Proteins; D023201:CD40 Ligand; D004958:Estradiol; D007371:Interferon-gamma