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Abstract: Plant secondary metabolites with estrogenic activity (phyto-estrogens) have been studied in the past as a potential alternative to classical hormone-replacement therapy (HRT) in menopausal women. No final verdict on the efficacy of soy or red clover based pharmaceutical preparations has been reached despite numerous clinical studies. We have studied the novel and most potent phyto-estrogen 8-prenylnaringenin (8-PN) in adult ovariectomized rats, an established animal model to mimic hormone dependent osteoporosis in menopausal women. Our results demonstrate that 8-PN can completely protect from ovariectomy induced bone-loss while exhibiting minimal, (dose independent) trophic effects on uterus and endometrium. It is estimated that at equivalent bone protective doses of 17β-estradiol and 8-PN, the phyto-estrogen has a 10-fold lower stimulatory effect on uterus and endometrium. The bone tissue specific effect of 8-PN was confirmed in a transgenic reporter mouse model (ERE-Luc mice). Here we also found pronounced estrogenic activity in prostate. Present results add important aspects to the pharmacological profile of 8-PN and position this compound as an interesting alternative new candidate for treatment of peri- and postmenopausal symptoms. [Copyright &y& Elsevier]

We have previously shown that 17β-estradiol (E2) prevents the activation of brain macrophages, i.e. microglia cells, both in vitro and in vivo. Hormone exerts this inhibitory effect by inhibiting pro-inflammatory gene expression. In this study we further investigated on the molecular mechanism of E2 action in the RAW 264.7 macrophage cell line. We show here that these cells express the α-isoform of the estrogen receptor (ERα) and not ERβ. Similarly to its activity in brain macrophages, E2 is able to inhibit the activation program induced by lipopolysaccharide (LPS) in RAW 264.7 cells, as shown by the inhibitory effect of hormone on the morphological conversion and matrix metalloproteinase-9 (MMP-9) expression induced by the endotoxin. In addition, we demonstrate that hormone treatment is not associated with a reduction in the steady-state expression of Toll-like receptor-4 (TLR-4) and CD14, two components of the LPS receptor complex. Our results further confirm the anti-inflammatory role of ERα in macrophages and propose that the mechanism of hormone action on macrophage reactivity involves signaling molecules which are down-stream effectors of the LPS membrane receptors. [Copyright &y& Elsevier]

Transforming growth factor-α (TGF-α) is known to promote both proliferation and differentiation of neural cell progenitors. Using the human neuroblastoma cell line SK-N-BE that is induced to proliferate by TGF-α, we demonstrated that the expression of a single transcription factor, the estrogen receptor-α (ERα), can reroute the TGF-α mitogenic signaling toward a path leading to differentiation. With selected mutations in ERα and signal transducer and activator of transcription 3 (Stat3), we demonstrated that the blockade of TGF-α mitotic potential was not dependent on ERα DNA binding activity but required a transcriptionally active Stat3. In neuroblastoma cells, 17β-estradiol treatment induced a transient increase in the transcription of estrogen-responsive element-containing promoters including those regulating TGF-α and prothymosin α synthesis. Based on the data presented, we hypothesized that in the presence of prothymosin α, ERα activates its direct target genes and increases cell proliferation, whereas in the presence of high levels of TGF-α, ERα preferentially interacts with Stat3 and causes cell differentiation. Our results reveal a novel form of "end-product" regulation of an intracellular receptor that occurs through recruitment of membrane receptors and their signaling effectar system. Cross-coupling between membrane and intracellular receptors has been described by several laboratories. This study proves the relevance of these interactions in cellular responses to growth factors. [ABSTRACT FROM AUTHOR]

Beyond the key role in reproductive and cognitive functions, estrogens have been shown to protect against neurodegeneration associated with acute and chronic injuries of the adult brain. Current hypotheses reconcile this activity with a direct effect of 17β-estradiol (E[sub 2]) on neurons. Here we demonstrate that brain macrophages are also involved in E[sub 2] action on the brain. Systemic administration of hormone prevents, in a time- and dose-dependent manner, the activation of microglia and the recruitment of peripheral monocytes induced by intraventricular injection of lipopolysaccharide. This effect occurs by limiting the expression of neuroinflammatory mediators, such as the matrix metalIoproteinase 9 and lysosomal enzymes and complement C3 receptor, as well as by preventing morphological changes occurring in microglia during the inflammatory response. By injecting lipopolysaccharide in estrogen receptor (ER)-null mouse brains, we demonstrate that hormone action is mediated by activation of ERα but not of ERβ. The specific role of ERα is further confirmed by comparing the effects of ERs on the matrix metalloproteinase 9 promoter activity in transient transfection assays. Finally, we report that genetic ablation of ERα is associated with a spontaneous reactive phenotype of microglia in specific brain regions of adult ERα-null mice. Altogether, these results reveal a previously undescribed function for E[sub 2] in brain and provide a mechanism for its beneficial activity on neuroinflammatory pathologies. They also underline the key role of ERα in brain macrophage reactivity and hint toward the usefulness of ERα-specific drugs in hormone replacement therapy of inflammatory diseases. [ABSTRACT FROM AUTHOR]

Through intracellular receptors, estrogens control growth, differentiation and function of not only reproductive tissues, but also other systems. Estrogen receptors are ligand-dependent transcription factors whose activity is modulated either by estrogens, or by alternative intracellular signaling pathways downstream of growth factors and neurotransmitters. To determine the dynamics of estrogen receptor activity and the dependence of estrogen receptor on 17β-estradiol in vivo, we generated a transgenic mouse that expresses a luciferase reporter gene under the control of activated estrogen receptors. As expected, luciferase activity, monitored with a cooled charged coupled device camera, paralleled circulating estrogen levels in reproductive tissues and in liver, indicating that the peak transcriptional activity of the estrogen receptor occurred at proestrus. In contrast, in tissues such as bone and brain, the peak activity of estrogen receptors was observed at diestrus. These tissue-specific responses are masked when mice undergo conventional hormone treatment. We also demonstrate that estrogen receptors are active in immature mice before gonadal production of sex hormones as well as in ovariectomized adult mice. These findings emphasize the importance of hormone-independent activation of the estrogen receptor, and have implications for the therapeutic use of estrogens, such as hormone replacement therapy. [ABSTRACT FROM AUTHOR]

Sex differences in immune-mediated diseases are linked to the activity of estrogens on innate immunity cells, including macrophages. Tamoxifen (TAM) is a selective estrogen receptor modulator (SERM) used in estrogen receptor-alpha (ERα)-dependent breast cancers and off-target indications such as infections, although the immune activity of TAM and its active metabolite, 4-OH tamoxifen (4HT), is poorly characterized. Here, we aimed at investigating the endocrine and immune activity of these SERMs in macrophages. Using primary cultures of female mouse macrophages, we analyzed the expression of immune mediators and activation of effector functions in competition experiments with SERMs and 17β-estradiol (E2) or the bacterial endotoxin LPS. We observed that 4HT and TAM induce estrogen antagonist effects when used at nanomolar concentrations, while pharmacological concentrations that are reached by TAM in clinical settings regulate the expression of VEGFα and other immune activation genes by ERα- and G protein-coupled receptor 1 (GPER1)-independent mechanisms that involve NRF2 through PI3K/Akt-dependent mechanisms. Importantly, we observed that SERMs potentiate cell phagocytosis and modify the effects of LPS on the expression of inflammatory cytokines, such as TNFα and IL1β, with an overall increase in cell inflammatory phenotype, further sustained by potentiation of IL1β secretion through caspase-1 activation. Altogether, our data unravel a novel molecular mechanism and immune functions for TAM and 4HT, sustaining their repurposing in infective and other estrogen receptors-unrelated pathologies. Tamoxifen activity in macrophages involves 1) estrogen receptor-α antagonism; 2) NRF2-mediated regulation of gene expression; 3) formation of active caspase-1; and 4) increased phagocytosis. [Display omitted] [ABSTRACT FROM AUTHOR]

People that the editors would like to thank for their assistance in the review of manuscripts for the journal in 2006 are presented.

Acknowledges several reviewers who assisted in the evaluation of manuscripts submitted for publication in "Neuroendocrinology" in 2000.