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 17␤-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-␣ 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-␣ 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 ␣, and interleukin-1␤ levels, 4) inducible nitric-oxide synthase, 5) lipid peroxidation, 6) nitrotyrosine formation, 7) cyclooxygenase expression, and 8) the IB-␣ 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-␣.The immune and inflammatory responses are complex physiological processes that are critically important to the homeostasis and ultimate survival of an organism. Their coordinate regulation must be assured to allow appropriate and timely immune reaction without an over-reaction that might cause damage to the host. The inflammatory process is invariably characterized by a production of prostaglandins, leukotrienes, histamine, bradykinin, platelet-activating factor and by a release of chemicals from tissues and migrating cells (Vane and Botting, 1987). Carrageenan-induced local inflammation is commonly used to evaluate the efficacy of nonsteroidal anti-inflammatory drugs. Therefore, carrageenan-induced local inflammation (pleurisy) is a useful model to assess the contribution of mediators involved in vascular changes associated with acute inflammation. In particular, the initial phase of acute inflammation (0 -1 h), which is not inhibited by nonsteroidal anti-inflammatory drugs such us indomethacin or aspirin, has been attributed to the release of histamine, 5-hydroxytryptamine, and bradykinin, followed S.C. and S.B. contributed equally to this work. Article, publication date, and citation information can be found at

ERα-mediated repression of pro-inflammatory cytokine expression by glucocorticoids reveals a critical role for TNFα and IL1α in lumen formation and maintenance.

“…Recently, the same group has demonstrated that ERa can drive pro-inflammatory cytokine repression caused by glucocorticoids (Cvoro et al, 2011). Accordingly, in vivo addition of estrogen receptor antagonist ICI182780 inhibits the anti-inflammatory effect of glucocorticoids in mice (Cuzzocrea et al, 2007). In line with the above evidence, we have found that addition of glucocorticoids caused an expected decrease in pro-inflammatory cytokine levels through ERa.…”

Cross Talk between Glucocorticoid and Estrogen Receptors Occurs at a Subset of Proinflammatory Genes

“…Despite the findings that both GR and ER repress proinflammatory cytokine genes, little is known about the potential cross talk between GR and ER. However, in an experimental lung inflammation rat model, the ER antagonist ICI 182780 (ICI) blocked the anti-inflammatory effects of glucocorticoids (19). This finding suggests that when ER is bound to an antagonist, it can cross talk with GR to block its anti-inflammatory action, but mechanism for this effect is unknown.…”

Peroxisome Proliferator-Activated Receptor-α Contributes to the Anti-Inflammatory Activity of Glucocorticoids

“…Multiple mechanisms are involved in GC-mediated anti-inflammatory activity in addition to direct GR/NF-B interaction, such as GC-induced up-regulation of IB and glucocorticoid-induced leucine zipper (GILZ), two proteins able to bind and inhibit NF-B activation (Ray and Prefontaine, 1994;Auphan et al, 1995;Scheinman et al, 1995;Cannarile et al, 2006;Di Marco et al, 2007). After NF-B inhibition, a number of inflammatory parameters are blocked, including cytokine production, cell migration, COX-2 and inducible nitric-oxide synthase (iNOS) activation, and tissue damage (Barnes and Karin, 1997;Yamamoto and Gaynor, 2001;Gilroy et al, 2004;Cuzzocrea et al, 2007).…”