Astrocyte-derived transforming growth factor-β mediates the neuroprotective effects of 17β-estradiol: Involvement of nonclassical genomic signaling pathways

Krishnan M. Dhandapani, F. Marlene Wade, Virendra B. Mahesh, Darrell W. Brann

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Abstract

17β-Estradiol (E2) and selective estrogen receptor modulators (SERMs), such as tamoxifen, mediate numerous effects in the brain, including neurosecretion, neuroprotection, and the induction of synaptic plasticity. Astrocytes, the most abundant cell type in the brain, influence many of these same functions and thus may represent a mediator of estrogen action. The present study examined the regulatory effect and underlying cell signaling mechanisms of E2-induced release of neurotropic growth factors from primary rat cortical astrocyte cultures. The results revealed that E2 (0.5, 1, and 10 nM) and tamoxifen (1 μM) increased both the expression and release of the nearoprotective cytokines, TGF-β1 and TGF-β2 (TGF-β), from cortical astrocytes. The stimulatory effect of E2 was attenuated by the estrogen receptor (ER) antagonist, ICI182,780, suggesting ER dependency. The effect of E2 also appeared to involve mediation by the phosphotidylinositol 3-kinase (PI3K)/Akt signaling pathway, because E2 rapidly induced Akt phosphorylation, and pharmacological or molecular inhibition of the PI3K/Akt pathway prevented E2-induced release of TGF-β. Additionally, the membrane-impermeant conjugate, E2-BSA, stimulated the release of TGF-β, suggesting the potential involvement of a membrane-bound ER. Finally, E2, tamoxifen, and E2-BSA were shown to protect neuronal-astrocyte cocultures from camptothecin-induced neuronal cell death, effects that were attenuated by ICI182,780, Akt inhibition, or TGF-β immunoneutralization. As a whole, these studies suggest that E2 induction of TGF-β release from cortical astrocytes could provide a mechanism of neuroprotection, and that E2 stimulation of TGF-β expression and release from astrocytes occurs via an ER-dependent mechanism involving mediation by the PI3K/Akt signaling pathway.

Original languageEnglish (US)
Pages (from-to)2749-2759
Number of pages11
JournalEndocrinology
Volume146
Issue number6
DOIs
StatePublished - Jun 1 2005

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Transforming Growth Factors
Neuroprotective Agents
Astrocytes
Estradiol
Tamoxifen
Estrogen Receptors
Phosphotransferases
Neurosecretion
Selective Estrogen Receptor Modulators
Camptothecin
Neuronal Plasticity
Membranes
Brain
Coculture Techniques
Intercellular Signaling Peptides and Proteins
Estrogens
Cell Death
Phosphorylation
Pharmacology
Cytokines

ASJC Scopus subject areas

  • Endocrinology

Cite this

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title = "Astrocyte-derived transforming growth factor-β mediates the neuroprotective effects of 17β-estradiol: Involvement of nonclassical genomic signaling pathways",
abstract = "17β-Estradiol (E2) and selective estrogen receptor modulators (SERMs), such as tamoxifen, mediate numerous effects in the brain, including neurosecretion, neuroprotection, and the induction of synaptic plasticity. Astrocytes, the most abundant cell type in the brain, influence many of these same functions and thus may represent a mediator of estrogen action. The present study examined the regulatory effect and underlying cell signaling mechanisms of E2-induced release of neurotropic growth factors from primary rat cortical astrocyte cultures. The results revealed that E2 (0.5, 1, and 10 nM) and tamoxifen (1 μM) increased both the expression and release of the nearoprotective cytokines, TGF-β1 and TGF-β2 (TGF-β), from cortical astrocytes. The stimulatory effect of E2 was attenuated by the estrogen receptor (ER) antagonist, ICI182,780, suggesting ER dependency. The effect of E2 also appeared to involve mediation by the phosphotidylinositol 3-kinase (PI3K)/Akt signaling pathway, because E2 rapidly induced Akt phosphorylation, and pharmacological or molecular inhibition of the PI3K/Akt pathway prevented E2-induced release of TGF-β. Additionally, the membrane-impermeant conjugate, E2-BSA, stimulated the release of TGF-β, suggesting the potential involvement of a membrane-bound ER. Finally, E2, tamoxifen, and E2-BSA were shown to protect neuronal-astrocyte cocultures from camptothecin-induced neuronal cell death, effects that were attenuated by ICI182,780, Akt inhibition, or TGF-β immunoneutralization. As a whole, these studies suggest that E2 induction of TGF-β release from cortical astrocytes could provide a mechanism of neuroprotection, and that E2 stimulation of TGF-β expression and release from astrocytes occurs via an ER-dependent mechanism involving mediation by the PI3K/Akt signaling pathway.",
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T1 - Astrocyte-derived transforming growth factor-β mediates the neuroprotective effects of 17β-estradiol

T2 - Involvement of nonclassical genomic signaling pathways

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AU - Mahesh, Virendra B.

AU - Brann, Darrell W.

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N2 - 17β-Estradiol (E2) and selective estrogen receptor modulators (SERMs), such as tamoxifen, mediate numerous effects in the brain, including neurosecretion, neuroprotection, and the induction of synaptic plasticity. Astrocytes, the most abundant cell type in the brain, influence many of these same functions and thus may represent a mediator of estrogen action. The present study examined the regulatory effect and underlying cell signaling mechanisms of E2-induced release of neurotropic growth factors from primary rat cortical astrocyte cultures. The results revealed that E2 (0.5, 1, and 10 nM) and tamoxifen (1 μM) increased both the expression and release of the nearoprotective cytokines, TGF-β1 and TGF-β2 (TGF-β), from cortical astrocytes. The stimulatory effect of E2 was attenuated by the estrogen receptor (ER) antagonist, ICI182,780, suggesting ER dependency. The effect of E2 also appeared to involve mediation by the phosphotidylinositol 3-kinase (PI3K)/Akt signaling pathway, because E2 rapidly induced Akt phosphorylation, and pharmacological or molecular inhibition of the PI3K/Akt pathway prevented E2-induced release of TGF-β. Additionally, the membrane-impermeant conjugate, E2-BSA, stimulated the release of TGF-β, suggesting the potential involvement of a membrane-bound ER. Finally, E2, tamoxifen, and E2-BSA were shown to protect neuronal-astrocyte cocultures from camptothecin-induced neuronal cell death, effects that were attenuated by ICI182,780, Akt inhibition, or TGF-β immunoneutralization. As a whole, these studies suggest that E2 induction of TGF-β release from cortical astrocytes could provide a mechanism of neuroprotection, and that E2 stimulation of TGF-β expression and release from astrocytes occurs via an ER-dependent mechanism involving mediation by the PI3K/Akt signaling pathway.

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