17β-Estradiol Promotes TLR4-Triggered Proinflammatory Mediator Production through Direct Estrogen Receptor α Signaling in Macrophages In Vivo
Abstract
17Beta-estradiol (E2) has been shown to promote the expression of inflammatory mediators by LPS-activated tissue resident macrophages through estrogen receptor alpha (ERalpha) 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-1beta, IL-6, and TNF-alpha) 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-1beta 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 ERalpha 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 ERalpha in macrophages in vivo, enhance their ability to produce inflammatory mediators and cytokines upon subsequent TLR activation.
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Low-dose E2 exposure (doses consistent with oral contraceptive pills) is associated with increased pro-inflammatory cytokine expression, while high doses (pregnancy levels) tend to generate an anti-inflammatory response.
“Both in vitro and in vivo studies show that while low dose exposure to E2 (doses consistent with oral contraceptive pills) is associated with increased pro-inflammatory cytokine expression [74, 76, 77], high doses (pregnancy levels) tend to generate an anti-inflammatory response [74].”
From Estrogen and thrombosis: a bench to bedside review (2020) · cites this paper as [76]
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Self-citation
- Authors
- Calippe, B., Douin-Echinard, V., Delpy, L., Laffargue, M., Lélu, K., Krust, A., Pipy, B., Bayard, F., Arnal, J.-F., Guéry, J.-C., & Gourdy, P.
- Affiliations
- Inserm (FR)
- Institut National de la Santé et de la Recherche Médicale Unité 858, Institut de Médecine Moléculaire de Rangueil, Institut Fédératif de Recherche 150, Université de Toulouse , Illkirch ,
- Centre National de la Recherche Scientifique (FR)
- Institut de génétique et de biologie moléculaire et cellulaire (FR)
- Université Toulouse III - Paul Sabatier (FR)
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-07
- Volume
- 185
- Issue
- 2
- Pages
- 1169-1176
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2113583367
- Cited by
- 245
- References
- 32
- Citations by year
- 2026: 11 · 2025: 8 · 2024: 16 · 2023: 9 · 2022: 19 · 2021: 27 · 2020: 18 · 2019: 10 · 2018: 16 · 2017: 15 · 2016: 22 · 2015: 21 · 2014: 14 · 2013: 10 · 2012: 12
- FWCI
- 6.84
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- estradiol, estrogen receptor alpha, macrophages, TLR4, lipopolysaccharide, inflammatory cytokines, inducible nitric oxide synthase, PI3K/Akt signaling, wortmannin, ovariectomy, peritoneal macrophages
- MeSH terms
- Animals, Cells, Cultured, Estradiol, Female, Flow Cytometry, Mice, Inbred C57BL, Thioglycolates, Blotting, Western, Signal Transduction, Cytokines, Macrophages, Peritoneal, Mice, Knockout, Inflammation Mediators, Phosphatidylinositol 3-Kinases, Reverse Transcriptase Polymerase Chain Reaction, Estrogen Receptor alpha, Proto-Oncogene Proteins c-akt, Toll-Like Receptor 4, Mice
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