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Molecular Pharmacology Fast Forward
First published on October 11, 2006; DOI: 10.1124/mol.106.029629

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Received for publication August 4, 2006.
Revised October 11, 2006.
Accepted for publication October 11, 2006.

ESTROGEN RECEPTOR ANTAGONIST ICI 182,780 INHIBITS THE ANTI-INFLAMMATORY EFFECT OF GLUCOCORTICOIDS

Salvatore cuzzocrea 1*, Stefano Bruscoli 2, Concetta Crisafulli 3, Emanuela Mazzon 3, Massimiliano Agostini 2, Carmelo Muia 3, Emanuela Espisito 4, Rosa Di Virgilio 2, Rosaria Meli 4, Elisabetta Vegeto 5, Adriana Maggi 5, Carlo Riccardi 5

1 University of messina 2 Univerita di Perugia 3 Univerita di Messina 4 Univerita di Napoli 5 Univerita di Milano

* Address correspondence to: E-mail: salvator{at}unime.it

Abstract

The glucocorticoid receptor (GR) and estrogen receptors (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 if ICI 182,780, a selective ER-{alpha} antagonist, is able to attenuate the well-known anti-inflammatory effect of dexamethasone (DEX, a synthetic glucocorticoid). We show that ICI 182,780, a selective ER-{alpha} antagonist, reverses the anti-inflammatory activity exhibited by DEX. Moreover, the co-administration of ICI 182,780 significantly inhibited the ability of DEX to reduce: (i) the degree of lung injury, (ii) the rise in myeloperoxidase (MPO) activity, (iii) the increase of poly(ADP-ribose) polymerase (PARP) activity, tumour necrosis factor alpha (TNF-{alpha}) and interleukin (IL)-1{beta} levels, (iv) inducible nitric oxide synthase (iNOS) and (v) cyclo-oxygenase (COX-2) expression (vi) the I{kappa}B-{alpha} degradation, caused by carrageenan administration. In conclusion these results suggest that the in vivo anti-inflammatory property of DEX is also related to the ER-{alpha}.


Key words: Glucorticoids/Mineralocorticoids, Sex hormones, NFkappaB, Oxidative stress


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S. Cuzzocrea, S. Bruscoli, E. Mazzon, C. Crisafulli, V. Donato, R. Di Paola, E. Velardi, E. Esposito, G. Nocentini, and C. Riccardi
Peroxisome Proliferator-Activated Receptor-{alpha} Contributes to the Anti-Inflammatory Activity of Glucocorticoids
Mol. Pharmacol., February 1, 2008; 73(2): 323 - 337.
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