title: Estrogen receptor antagonist fulvestrant (ICI 182,780) inhibits the anti-inflammatory effect of glucocorticoids.
abstract: 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 17beta-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-1beta levels, 4) inducible nitric-oxide synthase, 5) lipid peroxidation, 6) nitrotyrosine formation, 7) cyclooxygenase expression, and 8) the IkappaB-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.
authors.affiliation: Department of Clinical and Experimental Medicine, School of Medicine, University of Messina, Messina, Italy. salvator@unime.it
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
authors.forename: Stefano
authors.initials: S
authors.lastname: Bruscoli
authors.forename: Concetta
authors.initials: C
authors.lastname: Crisafulli
authors.forename: Emanuela
authors.initials: E
authors.lastname: Mazzon
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Agostini
authors.forename: Carmelo
authors.initials: C
authors.lastname: Muià
authors.forename: Emanuela
authors.initials: E
authors.lastname: Esposito
authors.forename: Rosa
authors.initials: R
authors.lastname: Di Virgilio
authors.forename: Rosaria
authors.initials: R
authors.lastname: Meli
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Vegeto
authors.forename: Adriana
authors.initials: A
authors.lastname: Maggi
authors.forename: Carlo
authors.initials: C
authors.lastname: Riccardi
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000037:antagonists & inhibitors*; D017931:DNA Primers; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D000077267:Fulvestrant; D005938:Glucocorticoids / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020239:Receptor Cross-Talk; D011960:Receptors, Estrogen / Q000502:physiology*; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D017931:DNA Primers; D004965:Estrogen Antagonists; D005938:Glucocorticoids; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; D000077267:Fulvestrant; D004958:Estradiol; D003907:Dexamethasone; D015232:Dinoprostone