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Cited by 187Immune Response and InflammationEstrogen and related hormone effectsNeuroinflammation and Neurodegeneration Mechanisms

Chronic estradiol administration in vivo promotes the proinflammatory response of macrophages to TLR4 activation: involvement of the phosphatidylinositol 3-kinase pathway

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Calippe, Bertrand, Douin-Echinard, Victorine, Laffargue, Muriel, Laurell, Henrik, Rana-Poussine, Vanessa, Pipy, Bernard, Guéry, Jean-Charles, Bayard, Francis +2 more·2008·The Journal of Immunology
DOI 10.4049/jimmunol.180.12.7980
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Abstract

Short-term exposure to 17beta-estradiol (E2) in vitro has been reported to decrease the production of proinflammatory cytokines by LPS-activated macrophages through estrogen receptor alpha (ERalpha)-dependent activation of the PI3K pathway. In the present study, we confirm that in vitro exposure of mouse peritoneal macrophages to E2 enhanced Akt phosphorylation and slightly decreased LPS-induced cytokine production. In striking contrast, we show that chronic administration of E2 to ovariectomized mice markedly increases the expression of IL-1beta, IL-6, IL-12p40, and inducible NO synthase by resident peritoneal macrophages in response to LPS ex vivo. These results clearly indicate that short-term E2 treatment in vitro does not predict the long-term effect of estrogens in vivo on peritoneal macrophage functions. We show that this in vivo proinflammatory effect of E2 was mediated through ERalpha. Although the expression of components of the LPS-recognition complex remained unchanged, we provided evidences for alterations of the TLR4 signaling pathway in macrophages from E2-treated mice. Indeed, E2 treatment resulted in the inhibition of PI3K activity and Akt phosphorylation in LPS-activated macrophages, whereas NF-kappaB p65 transcriptional activity was concomitantly increased. Incubation of macrophages with the PI3K inhibitor wortmanin enhanced proinflammatory cytokine gene expression in response to TLR4 activation, and abolishes the difference between cells from placebo- or E2-treated mice, demonstrating the pivotal role of the PI3K/Akt pathway. We conclude that the macrophage activation status is enhanced in vivo by E2 through ERalpha and, at least in part, by the down-modulation of the PI3K/Akt pathway, thereby alleviating this negative regulator of TLR4-signaling.

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  • Short-duration E2 treatment (2-6 hours) has an anti-inflammatory effect, while chronic administration over 60 days is associated with a pro-inflammatory response.

    “Similarly, a short duration of E2 treatment (2–6 hours) has an anti-inflammatory effect [78, 79], while chronic administration over 60 days is associated with a pro-inflammatory response [77].”

    From Estrogen and thrombosis: a bench to bedside review (2020) · cites this paper as [77]

  • 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 [77]

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Authors
Calippe, B., Douin-Echinard, V., Laffargue, M., Laurell, H., Rana-Poussine, V., Pipy, B., Guéry, J.-C., Bayard, F., Arnal, J.-F., & Gourdy, P.
Affiliations
  • Inserm (FR)
  • Institut National de la Santé et de la Recherche Médicale U858, Institut de Médecine Moléculaire de Rangueil, IFR31 , Toulouse
  • Université Toulouse III - Paul Sabatier (FR)
  • Institut National de la Santé et de la Recherche Médicale U563, Centre de Physiopathologie de Toulouse Purpan, IFR30 , Toulouse
Corresponding author
  • Calippe, Bertrand
  • Laurell, Henrik
  • Bayard, Francis
  • Gourdy, Pierre
ORCID
Venue
The Journal of Immunology
Publisher
Oxford University Press (OUP)
Published
2008-06
Volume
180
Issue
12
Pages
7980-7988
ISSN
  • 0022-1767 (ISSN-L)
  • 1550-6606
DOI
10.4049/jimmunol.180.12.7980
OpenAlex
W1930249563
Cited by
187
References
34
Citations by year
2026: 3 · 2025: 7 · 2024: 5 · 2023: 5 · 2022: 8 · 2021: 23 · 2020: 12 · 2019: 11 · 2018: 10 · 2017: 11 · 2016: 16 · 2015: 8 · 2014: 11 · 2013: 5 · 2012: 16
FWCI
5.15
Type
journal article
Language
en
Open access
Licence
academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations
  • The Journal of Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Funders
  • Agence Nationale de la Recherche
  • Fondation de France
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
estradiol, estrogen receptor alpha, macrophages, TLR4 signaling, PI3K/Akt signaling, inflammatory cytokines, lipopolysaccharide, NF-κB p65, wortmannin, ovariectomy, inducible nitric oxide synthase, IL-1β, interleukin-6, IL-12p40, macrophage activation
MeSH terms
Phosphoinositide-3 Kinase Inhibitors, Administration, Cutaneous, Animals, Cells, Cultured, Delayed-Action Preparations, Drug Implants, Estradiol, Female, Lipopolysaccharides, Macrophage Activation, Mice, Inbred C57BL, Time Factors, Signal Transduction, Cytokines, Macrophages, Peritoneal, Mice, Knockout, Inflammation Mediators, Phosphatidylinositol 3-Kinases, Estrogen Receptor alpha, Toll-Like Receptor 4, Mice

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