Supraphysiological level of estrogen exposure in vivo increases lymphoid cell death in mice

Zajchowski, Sheri; Hoffman‐Goetz, Laurie

doi:10.1016/s0024-3205(00)00456-2

Cited by 18 publications

(13 citation statements)

References 22 publications

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“…44). Although some studies have shown mild increases in the percentage of apoptotic thymocytes after estradiol treatment (12,45), others have been unable to detect significant DNA fragmentation over a broad time course, during which maximal thymic atrophy is occurring (17). Staples et al (14) have shown that in contrast to glucocorticoid-mediated thymic atrophy, overexpression of Bcl-2 does not rescue mice from estradiol-induced atrophy, indicating a pathway divergent from that used by glucocorticoids.…”

Section: Discussionmentioning

confidence: 99%

Estrogen Induces Thymic Atrophy by Eliminating Early Thymic Progenitors and Inhibiting Proliferation of β-Selected Thymocytes

Zoller

Kersh

2006

The Journal of Immunology

121

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Although it has been established that high levels of estrogen can induce thymic involution, the mechanism by which this happens is not known. We have found that daily i.p. injections of the synthetic estrogen 17-β-estradiol reduce thymus cellularity by 80% over a period of 4–6 days. Although the atrophy is most strikingly observed in the CD4/CD8 double-positive (DP) thymic subset, the loss of thymocytes is not accompanied by a significant increase in thymocyte apoptosis, suggesting that direct killing of cells may not be the dominant means by which estrogens induce thymic atrophy. Instead, we find that estradiol drastically reduces the lineage-negative, Flt3+Sca-1+c-Kit+ population in the bone marrow, a population that contains thymic homing progenitors. Within the thymus, we observe that estradiol treatment results in a preferential depletion of early thymic progenitors. In addition, we find that estradiol leads to a significant reduction in the proliferation of thymocytes responding to pre-TCR signals. Reduced proliferation of DN3 and DN4 cell subsets is likely the major contributor to the reduction in DP thymocytes that is observed. The reduction in early thymic progenitors is also likely to contribute to thymic atrophy, as we show that estradiol treatment can reduce the size of Rag1-deficient thymuses, which lack pre-TCR signals and DP thymocytes.

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Section: Discussionmentioning

confidence: 99%

Estrogen Induces Thymic Atrophy by Eliminating Early Thymic Progenitors and Inhibiting Proliferation of β-Selected Thymocytes

Zoller

Kersh

2006

The Journal of Immunology

121

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“…Original magnification 1,560 Â . Ozan, 2002) as well as clonal expansion, and stimulation of programmed cell death (Staples et al, '98;Zajchowski and Hoffman-Goetz, 2000;Hoffman-Goetz et al, 2001;Jenkins et al, 2001;McMurray et al, 2001;Okasha et al, 2001;Patel and Hoffman-Goetz, 2002). in the wall lizard, E 2 treatment markedly decreased the Con-A-induced thymocyte proliferation in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

“…The administration of testosterone in castrated animals is reported to cause thymic involution with a marked depletion of thymocytes (Varas et al, '91;Hareramadas and Rai, 2001). In mammals, various mechanisms have been implicated in the process of thymic atrophy in response to sex steroids, e.g., inhibition of thymocyte proliferation and/or increase in thymocyte trafficking and cell death (Staples et al, '98;Zajchowski and Hoffman-Goetz, 2000;HoffmanGoetz et al, 2001;Jenkins et al, 2001;McMurray et al, 2001;Okasha et al, 2001;Patel and Hoffman-Goetz, 2002). In the ectothermic vertebrates, no report is available on the cellular mechanism of sex steroids-induced thymic atrophy, except our earlier study in wall lizards that deals with testosterone (Hareramadas and Rai, 2005).…”

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confidence: 93%

Cellular mechanism of estrogen‐induced thymic involution in wall lizard: caspase‐dependent action

Hareramadas¹,

Rai²

2006

J. Exp. Zool.

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The present study, for the first time in an ectothermic vertebrate, demonstrates the cellular mechanism of estrogen-induced thymic involution. Ovariectomy in lizards during the preparatory phase of the reproductive cycle resulted in distinct differentiation of cortico-medullary regions and increase in cellularity, especially in the cortical region. The ovariectomy-induced changes were reversed following administration of 17-estradiol (E2), suggesting a primary role of E2 in causing thymic atrophy. To understand the cellular mechanism of E2-induced thymic atrophy, in vitro effect of E2 was investigated on thymocyte proliferation and apoptosis. E2 decreased the uptake of tritiated thymidine (3H-TdR) by thymocytes in a dose-dependent manner, suggesting that estrogen directly inhibits the thymocyte proliferation. Unlike proliferation, E2 did not have any direct effect on thymocyte apoptosis, as evident by DNA gel electrophoretic, flow cytometric or fluorescence microscopic studies. However, in the presence of thymic epithelial cell-rich stromal components (TEC), E2 treatment at low or high concentrations resulted in depolarization of plasma membrane, DNA fragmentation and decrease in DNA content. This suggests that E2 indirectly, through TEC-secreted factors, controls thymocyte apoptosis. Similar result was observed following fluorescence microscopy. The indirect effect of E2 was further ascertained with the findings that E2-pretreated TEC-conditioned medium accelerated the thymocyte apoptosis. Nevertheless, exposure of thymocytes to E2 was seen to be inevitable for the apoptotic action of TEC-secreted paracrine factors. In the presence of TEC, a positive reaction for caspase-3, -7 and -9 and enzyme substrate, poly(ADP-ribose) polymerase (PARP) in response to E2 suggests the caspase-dependent thymocyte apoptosis in the wall lizard Hemidactylus flaviviridis. Further, E2 was shown to act through genomic pathway, since the receptor antagonist tamoxifen and transcription/translation inhibitors blocked its apoptotic action. Interestingly, the apoptotic effect of E2 was effectively decreased by progesterone.

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“…Estrogens, in particular 17-␤ estradiol (E 2 ), are well-characterized mitogens for mammary tissues and epithelial cells of the female reproductive tract. Whereas estrogens exert antiapoptotic influence in neurons (Zhang et al, 2001), epithelial cells of the female reproductive tract (Leung and Wang, 1999;Choi et al, 2001), immune system, blood cells, and endothelial cells (Bynoe et al, 2000;Haynes et al, 2000), they also have significant apoptotic effects on certain classes of bone-derived cells (Hughes et al, 1996;Kameda et al, 1997) and some immune system cells (Zajchowski and Hoffman-Goetz, 2000;Okasha et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Estradiol Abrogates Apoptosis in Breast Cancer Cells through Inactivation of BAD: Ras-dependent Nongenomic Pathways Requiring Signaling through ERK and Akt

Fernando

Wimalasena

2004

MBoC

113

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Estrogens such as 17-β estradiol (E2) play a critical role in sporadic breast cancer progression and decrease apoptosis in breast cancer cells. Our studies using estrogen receptor-positive MCF7 cells show that E2 abrogates apoptosis possibly through phosphorylation/inactivation of the proapoptotic protein BAD, which was rapidly phosphorylated at S112 and S136. Inhibition of BAD protein expression with specific antisense oligonucleotides reduced the effectiveness of tumor necrosis factor-α, H2O2, and serum starvation in causing apoptosis. Furthermore, the ability of E2 to prevent tumor necrosis factor-α-induced apoptosis was blocked by overexpression of the BAD S112A/S136A mutant but not the wild-type BAD. BAD S112A/S136A, which lacks phosphorylation sites for p90RSK1 and Akt, was not phosphorylated in response to E2 in vitro. E2 treatment rapidly activated phosphatidylinositol 3-kinase (PI-3K)/Akt and p90RSK1 to an extent similar to insulin-like growth factor-1 treatment. In agreement with p90RSK1 activation, E2 also rapidly activated extracellular signal-regulated kinase, and this activity was down-regulated by chemical and biological inhibition of PI-3K suggestive of cross talk between signaling pathways responding to E2. Dominant negative Ras blocked E2-induced BAD phosphorylation and the Raf-activator RasV12T35S induced BAD phosphorylation as well as enhanced E2-induced phosphorylation at S112. Chemical inhibition of PI-3K and mitogen-activated protein kinase kinase 1 inhibited E2-induced BAD phosphorylation at S112 and S136 and expression of dominant negative Ras-induced apoptosis in proliferating cells. Together, these data demonstrate a new nongenomic mechanism by which E2 prevents apoptosis.

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Supraphysiological level of estrogen exposure in vivo increases lymphoid cell death in mice

Cited by 18 publications

References 22 publications

Estrogen Induces Thymic Atrophy by Eliminating Early Thymic Progenitors and Inhibiting Proliferation of β-Selected Thymocytes

Estrogen Induces Thymic Atrophy by Eliminating Early Thymic Progenitors and Inhibiting Proliferation of β-Selected Thymocytes

Cellular mechanism of estrogen‐induced thymic involution in wall lizard: caspase‐dependent action

Estradiol Abrogates Apoptosis in Breast Cancer Cells through Inactivation of BAD: Ras-dependent Nongenomic Pathways Requiring Signaling through ERK and Akt

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