Regulation of the lipopolysaccharide signal transduction pathway by 17β-estradiol in macrophage cells

Vegeto, Elisabetta; Ghisletti, Serena; Meda, Clara; Etteri, Sabrina; Belcredito, Silvia; Maggi, Adriana

doi:10.1016/j.jsbmb.2004.02.004

Cited by 95 publications

(66 citation statements)

References 39 publications

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“…In line with the recently identified proinflammatory effect of in vivo E2 treatment on murine resident peritoneal macrophages and microglial cells (9,10), the current study demonstrates that chronic exposure to estrogens enhances the production of various proinflammatory mediators by TGC elicited (i.e., "inflamed" peritoneal macrophages), contrasting with the anti-inflammatory effect of a short-term exposition to the hormone in vitro, previously reported in the same cell types (6)(7)(8). Altogether, these observations clearly demonstrate that the experimental results obtained with a short-term E2 treatment in vitro are not predictive of the effect of a long-term exposure to estrogens in vivo on macrophage functions.…”

Section: Discussionsupporting

confidence: 89%

“…Conflicting results have been reported from studies investigating the effects of estrogens on macrophage effector functions. Whereas in vitro experiments have suggested that E2 exerts anti-inflammatory properties on monocyte/macrophage cell lines or microglial cells following their activation with LPS, the prototypic ligand of TLR4 (5)(6)(7)(8), opposite results have been independently reported by analyzing the in vivo effects of estrogens on the same cell populations (9,10). Indeed, in striking contrast with previous in vitro observations, long-term in vivo exposure to estrogens from endogenous or exogenous origin was first demonstrated to enhance the LPS-induced transcription of proinflammatory cytokines, namely IL-12 and TNF-a, by microglial cells through ERa-dependent mechanisms (10).…”

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confidence: 99%

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17β-Estradiol Promotes TLR4-Triggered Proinflammatory Mediator Production through Direct Estrogen Receptor α Signaling in Macrophages In Vivo

Calippe

Douin‐Echinard

Delpy

et al. 2010

The Journal of Immunology

216

147

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17β-estradiol (E2) has been shown to promote the expression of inflammatory mediators by LPS-activated tissue resident macrophages through estrogen receptor α (ERα) signaling. However, it remained to be determined whether E2 similarly influences macrophages effector functions under inflammatory conditions in vivo, and whether this action of E2 resulted from a direct effect on macrophages. We show in this study that chronic E2 administration to ovariectomized mice significantly increased both cytokine (IL-1β, IL-6, and TNF-α) and inducible NO synthase mRNA abundance in thioglycolate (TGC)-elicited macrophages. The proinflammatory action of E2 was also evidenced at the level of released IL-1β and IL-6 by ex vivo LPS-activated macrophages. E2 concomitantly inhibited PI3K activity as well as Akt phosphorylation in TGC-elicited macrophages, suggesting that E2 promoted TLR-dependent macrophage activation by alleviating this suppressive signaling pathway. Indeed, this effect was abolished in the presence of the inhibitor wortmannin, demonstrating a key functional link between inhibition of PI3K activity and the E2 action on macrophage functions. Endogenous estrogens levels circulating in ovary-intact mice were sufficient to promote the above described actions. Finally, thanks to a CreLox strategy, targeted disruption of ERα gene in macrophages totally abolished the effect of E2 on the expression of inflammatory mediators by both resident and TGC-elicited peritoneal macrophages. In conclusion, we demonstrate that estrogens, through the activation of ERα in macrophages in vivo, enhance their ability to produce inflammatory mediators and cytokines upon subsequent TLR activation.

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Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 99%

17β-Estradiol Promotes TLR4-Triggered Proinflammatory Mediator Production through Direct Estrogen Receptor α Signaling in Macrophages In Vivo

Calippe

Douin‐Echinard

Delpy

et al. 2010

The Journal of Immunology

216

147

View full text Add to dashboard Cite

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“…How this is reflected in longer-term effects of estrogen on bone turnover is unclear at this point, but estrogen-dependent maintenance of ER␣ receptors would be expected to facilitate the estrogen response. We were unable to detect ER␤ in RAW264.7 cells, a finding that is consistent with results in both murine and human osteoclast precursors (10,11). There is some controversy on this point because antibody-based studies have reported ER␤ in human osteoclasts (8,9).…”

Section: Fig 5 Effect Of Estrogens and Phytoestrogens On Cell Cyclesupporting

confidence: 84%

“…ER␣ is present in osteoclasts (7), whereas ER␤ is controversial. By immune localization, ER␤ is reported in the nuclei of human osteoclasts (8,9), but only ER␣ is reported to be found in isolated human osteoclast precursors or murine pre-osteoclastic RAW264.7 cells (10,11). Available precedents suggest that the effects of estrogen on osteoclast progenitors and osteoclast differentiation may be more important than the effects on formed osteoclasts (12)(13)(14).…”

mentioning

confidence: 99%

Negative Regulation of RANKL-induced Osteoclastic Differentiation in RAW264.7 Cells by Estrogen and Phytoestrogens

Palacios

Robinson

Borysenko

et al. 2005

Journal of Biological Chemistry

106

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We studied estrogen effects on osteoclastic differentiation using RAW264.7, a murine monocytic cell line. Differentiation, in response to RANKL and colony-stimulating factor 1, was evaluated while varying estrogen receptor (ER) stimulation by estradiol or nonsteroidal ER agonists was performed. The RAW264.7 cells were found to express ER␣ but not ER␤. In contrast to RANKL, which decreased ER␣ expression and induced osteoclast differentiation, 10 nM estradiol, 3 M genistein, or 3 M daidzein all increased ER␣ expression, stimulated cell proliferation, and decreased multinucleation, with the effects of estrogen > daidzein > genistein. However, no estrogen agonist reduced RANKL stimulation of osteoclast differentiation markers or its down-regulation of ER␣ expression by more than ϳ50%. Genistein is also an Src kinase antagonist in vitro, but it did not decrease Src phosphorylation in RAW264.7 cells relative to other estrogen agonists. However, both phytoestrogens and estrogen inhibited RANKL-induced IB degradation and NF-B nuclear localization with the same relative potency as seen in proliferation and differentiation assays. This study demonstrates, for the first time, the direct effects of estrogen on osteoclast precursor differentiation and shows that, in addition to effecting osteoblasts, estrogen may protect bone by reducing osteoclast production. Genistein, which activates ERs selectively, inhibited osteoclastogenesis less effectively than the nonselective phytoestrogen daidzein, which effectively reproduced effects of estrogen.Estrogen is a key regulator of skeletal mass. Most estrogen effects are mediated by estrogen receptors (ERs) 1 ␣ and ␤, which are ligand-dependent transcriptional regulators. ER␣, the classical sex-related receptor, has a wide tissue distribution and is found in osteoclasts and osteoclast precursors as well as osteoblasts; ER␤ is primarily found in epithelial and mesenchymal tissues, including the mesenchymal stem cell-derived bone-forming cells, osteoblasts. There are also estrogen-binding proteins that are not transcription factors, and some estrogenic effects are mediated by membrane receptors linked to calcium (1, 2). The effects of estrogens on skeletal cells are complex, and the mechanism(s) of action are controversial (reviewed in Ref.3). However, transgenic and knock-out mice with varying ER␣ and ER␤ expression established that estrogen effects on bone involve ER␣ and ER␤, which modulate signaling pathways involving Erk and nitric oxide and perform direct transcriptional activity (4). Estrogen responses in mesenchymal stem cell-derived bone-forming cells, osteoblasts, are extensively studied. The effects of estrogens on osteoblasts include regulation of synthesis of the osteoclast differentiation factor RANKL relative to its inhibitor osteoprotegerin (5, 6), which may secondarily regulate osteoclast formation and activity.In contrast, primary estrogen effects on osteoclast differentiation and function are largely uncharacterized. ER␣ is present in osteoclasts (7), whereas ER␤ is...

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“…Furthermore, other studies have documented that TLR4 expression on innate immune system cells after in vitro exposure to oestrogens was not altered (Vegato et al 2004;Pioli et al 2007;Rettew et al 2009) whereas in vivo oestrogens augment TLR4 expression on murine macrophages (Rettew et al 2009). …”

Section: Discussionmentioning

confidence: 97%

The effects of in vitro exposure to progesterone and estradiol-17β on the activity of canine neutrophils

Bartošková¹,

Ondráčková²,

Levá³

et al. 2014

Vet. Med. - Czech

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ABSTRACT:To date, only limited information about the influence of ovarian hormones on canine immune system cells has been available. The study investigated the in vitro influence of progesterone and estradiol-17β on the activity of canine neutrophils. Treatment of cells by both hormones led to a significant decrease in phagocytosisinduced oxidative burst as detected using luminometry after stimulation with opsonised zymosan. The increase in oxidative burst, not connected with phagocytosis, was recorded after stimulation with a soluble stimulator. Using flow cytometry, the tendency of both hormones to decrease the production of reactive oxygen species associated with phagocytosis of Escherichia coli was also evident, although not significant. Suppression of canine neutrophil activity is not connected with pathogen recognition capabilities, since the expression of Toll-like receptor 4 was unaffected. This study reveals that both hormones have a suppressive effect on the activity of canine neutrophils and thus might contribute to the aetiology of pyometra.

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Regulation of the lipopolysaccharide signal transduction pathway by 17β-estradiol in macrophage cells

Cited by 95 publications

References 39 publications

17β-Estradiol Promotes TLR4-Triggered Proinflammatory Mediator Production through Direct Estrogen Receptor α Signaling in Macrophages In Vivo

17β-Estradiol Promotes TLR4-Triggered Proinflammatory Mediator Production through Direct Estrogen Receptor α Signaling in Macrophages In Vivo

Negative Regulation of RANKL-induced Osteoclastic Differentiation in RAW264.7 Cells by Estrogen and Phytoestrogens

The effects of in vitro exposure to progesterone and estradiol-17β on the activity of canine neutrophils

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