Selective estrogen receptor modulators decrease the production of interleukin‐6 and interferon‐γ‐inducible protein‐10 by astrocytes exposed to inflammatory challenge in vitro

Abstract

Expression of proinflammatory molecules by glial cells is involved in the pathophysiological changes associated with chronic neurological diseases. Under pathological conditions, astrocytes release a number of proinflammatory molecules, such as interleukin-6 (IL-6) and interferon-gamma-inducible protein-10 (IP-10). The ovarian hormone estradiol exerts protective effects in the central nervous system that, at least in part, may be mediated by a reduction of local inflammation. This study was designed to assess whether estradiol affects the production of IL-6 and IP-10 by primary cultures of newborn mice astrocytes exposed to lipopolysaccharide (LPS), a bacterial endotoxin known to cause neuroinflammation. In addition, the possible anti-inflammatory effect of several selective estrogen receptor modulators (SERMs) was also assessed. LPS induced an increase in the expression of IL-6 and IP-10 mRNA levels in astrocytes and an increase in IL-6 and IP-10 protein levels in the culture medium. These effects of LPS were impaired by estradiol and by the four SERMs tested in our study: tamoxifen, raloxifene, ospemifene, and bazedoxifene. All SERMs tested showed a similar effect on IL-6 and IP-10 mRNA levels, but raloxifene and ospemifene were more effective than tamoxifen and bazedoxifene in reducing protein levels in LPS-treated cultures. Finally, we report that news SERMs, ospemifene and bazedoxifene, exert anti-inflammatory actions by a mechanism involving classical estrogen receptors and by the inhibition of LPS-induced NFkappaB p65 transactivation. The results suggest that estrogenic compounds may be candidates to counteract brain inflammation under neurodegenerative conditions by targeting the production and release of proinflammatory molecules by astrocytes.

Melatonin and oestrogen treatments were able to improve neuroinflammation and apoptotic processes in dentate gyrus of old ovariectomized female rats

“…Oestrogen receptor (ER) and NFκB family members have been shown to influence each other's transcriptional activity. Much work has been done to delineate the multiple mechanisms by which ER could repress NFκB action to exert an anti-inflammatory effect (Kalaitzidis and Gilmore 2005;Cerciat et al 2010).…”

Gender and the Pathogenesis of Gastrointestinal Diseases: The Role of Steroid Sex Hormones in the Development

“…Vascularsmooth muscle and endothelial cells have been reported to express ERα and Erβ protein & mRNA [34][35][36]. Oestrogen has been proved to have anti-inflammatory effect by acting against inflammatory promoters, such as bacterial cell wall component, lipopolysaccharide (LPS) via activating ERα [37][38][39][40][41][42].…”

Estrogen-mediated protection of experimental autoimmune encephalomyelitis: Lessons from the dissection of estrogen receptor-signaling in vivo

“…[31,74] Altogether, these observations suggest that differences in ER-specific ligands are not only the result of distinct pharmacological effects, but that each ligand may have different cellular targets. Interestingly, selective estrogen receptor modulators (SERMs) such as raloxifene and bazedoxifene have been recently shown to inhibit inflammatory mediator production by reactive astrocytes in vitro, which holds therapeutic promise against neuroinflammation in MS. [77,78] Taken together, these results indicate that beside the anti-inflammatory actions of E2/ERα in the periphery, estrogens or ER selective agonists may also mediate neuroprotective effects through classical ERα or ERβ expressed by distinct cellular targets in the CNS [ Figure 1]. Although neuroprotective effects of E2 or ER-specific ligands have been shown in experimental models where mice were treated after chronic EAE onset [30] or using adoptive transfer of encephalitogenic CD4 T-cells, [74] it is still unclear whether the neuroprotective effects of ERα ligands, for instance, could still be observed in the complete absence of anti-inflammatory actions due to immune cell targeting in the periphery.…”