Estrogen receptor antagonist fulvestrant (ICI 182,780) inhibits the anti-inflammatory effect of glucocorticoids

被引:24
作者
Cuzzocrea, Salvatore [1 ]
Bruscoli, Stefano
Crisafulli, Concetta
Mazzon, Emanuela
Agostini, Massimiliano
Muia, Carmelo
Esposito, Emanuela
Di Virgilio, Rosa
Meli, Rosaria
Vegeto, Elisabetta
Maggi, Adriana
Riccardi, Carlo
机构
[1] Policlin Univ, Dipartimento Clin & Sperimentale Med & Farmacol, Sch Med, I-98123 Messina, Italy
[2] Ist Ricovero & Cura Carattere Sci Ctr Neurolesi B, Messina, Italy
[3] Univ Perugia, Dept Clin & Expt Med, Pharmacol Toxicol & Chemotherapy Sect, I-06100 Perugia, Italy
[4] Univ Naples Federico II, Dept Expt Pharmacol, Naples, Italy
[5] Univ Milan, Dept Pharmacol Sci, Ctr Excellence Neurodegenerat Dis, Milan, Italy
关键词
D O I
10.1124/mol.106.029629
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The glucocorticoid receptor (GR) and estrogen receptor (ER) play important roles in both physiological and pathological conditions involving cell growth and differentiation, lipolysis, control of glucose metabolism, immunity, and inflammation. In fact, recent studies suggest that 17 beta-estradiol, like glucocorticoids, may also have anti-inflammatory properties, even if the molecular mechanisms responsible for these activities have not yet been completely clarified. The present study was designed to gain a better understanding of the possible cross-talk between GR and ER in a model of lung inflammation (carrageenan-induced pleurisy). In particular, we have investigated whether fulvestrant (ICI 182,780), a selective ER-alpha antagonist, is able to attenuate the well known anti-inflammatory effect of dexamethasone (DEX), a synthetic glucocorticoid, in ovariectomized rats. We show that ICI 182,780, a selective ER-alpha antagonist, reverses the anti-inflammatory activity exhibited by DEX. Moreover, the coadministration of ICI 182,780 significantly inhibited the ability of DEX to reduce: 1) the degree of lung injury, 2) the rise in myeloperoxidase activity, 3) the increase of poly(ADP-ribose) polymerase activity, tumor necrosis factor alpha, and interleukin-1 beta levels, 4) inducible nitric-oxide synthase, 5) lipid peroxidation, 6) nitrotyrosine formation, 7) cyclooxygenase expression, and 8) the I kappa B-alpha degradation caused by carrageenan administration. In addition, quantitative PCR shows that DEX down-regulates GR and up-regulates glucocorticoid-induced leucine zipper levels, whereas ICI 182,780 does not counteract these effects. In conclusion, these results suggest that the in vivo anti-inflammatory property of DEX is also related to the ER-alpha.
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页码:132 / 144
页数:13
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