Estradiol binding to cell surface raises cytosolic free calcium in T cells

Benten, W. Peter M.; Lieberherr, Michèle; Giese, Günter; Wunderlich, Frank

doi:10.1016/s0014-5793(98)00039-8

Cited by 136 publications

(97 citation statements)

References 32 publications

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“…To date, the precise location of membrane-associated ER is a matter of debate, i.e., it has not been determined whether the membraneassociated ER binding site is on the inner or outer leaflet of the plasma membrane. Several investigators, using a variety of ER-specific antibodies in intact, nonpermeabilized cells, have hypothesized that the expression of ER occurs at the external leaflet of the cell membrane (38)(39)(40)(41)(42)(43)(44)(45). Conversely, other research groups have pointed to the cytoplasmic tail of membrane-associated ER as a key functional domain (8).…”

Section: Discussionmentioning

confidence: 99%

Autoantibodies to estrogen receptor α interfere with T lymphocyte homeostasis and are associated with disease activity in systemic lupus erythematosus

Colasanti¹,

Maselli²,

Conti³

et al. 2012

Arthritis & Rheumatism

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Objective. Estrogens influence many physiologic processes and are also implicated in the development or progression of numerous diseases, including autoimmune disorders. Aberrations of lymphocyte homeostasis that lead to the production of multiple pathogenic autoantibodies, including autoantibodies specific to estrogen receptor (ER), have been detected in the peripheral blood of patients with systemic lupus erythematosus (SLE). This study was undertaken to assess the presence of both anti-ER␣ and anti-ER␤ antibodies in sera from patients with SLE, to analyze the effect of these antibodies on peripheral blood T lymphocyte homeostasis, and to evaluate their role as determinants of disease pathogenesis and progression.Methods. Anti-ER antibody serum immunoreactivity was analyzed by enzyme-linked immunosorbent assay in samples from 86 patients with SLE and 95 healthy donors. Phenotypic and functional analyses were performed by flow cytometry and Western blotting.Results. Anti-ER␣ antibodies were present in 45% of the patients with SLE, whereas anti-ER␤ antibodies were undetectable. In healthy donors, anti-ER␣ antibodies induced cell activation and consequent apoptotic cell death in resting lymphocytes as well as proliferation of anti-CD3-stimulated T lymphocytes. A significant association between anti-ER␣ antibody values and clinical parameters, i.e., the SLE Disease Activity Index and arthritis, was found.Conclusion. Our data suggest that anti-ER␣ autoantibodies interfere with T lymphocyte homeostasis and are significantly associated with lupus disease activity.The involvement of estrogens, which influence many physiologic processes, has been shown in the development or progression of several autoimmune disorders (1-4). There is evidence that 17␤-estradiol directly modulates the development and function of immune cells, although the mechanism by which this might occur is not well understood (5,6). The primary mechanism of 17␤-estradiol activity is mediated by transcription activity of the intracellular estrogen receptors (ERs), ER␣ and ER␤, to produce genomic effects (7). A variety of cellular responses to physiologic concentrations of 17␤-estradiol occur rapidly, within seconds to a few minutes. These rapid estrogen-mediated effects (referred to as nongenomic) are triggered through the activation of membrane-associated ER and are independent of transcription pathways and protein synthesis.

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Section: Discussionmentioning

confidence: 99%

Autoantibodies to estrogen receptor α interfere with T lymphocyte homeostasis and are associated with disease activity in systemic lupus erythematosus

Colasanti¹,

Maselli²,

Conti³

et al. 2012

Arthritis & Rheumatism

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“…The activation of gene transcription by estrogen requires ER dimerization and binding to an estrogen response element (ERE), followed by activation of transcription factors and cofactors (58). ERs are expressed in a variety of immunocompetent cells, including T cells and macrophages (21,59,60), and EREs have been identified in a number of immunologically relevant genes. For example, an ERE has been mapped to the 5Ј-flanking sequence of the IFN-␥ gene, and estrogen has been shown to induce transcription of genes containing this ERE (61).…”

Section: Discussionmentioning

confidence: 99%

Estrogen Treatment Down-Regulates TNF-α Production and Reduces the Severity of Experimental Autoimmune Encephalomyelitis in Cytokine Knockout Mice

Ito¹,

Bebo

Matejuk³

et al. 2001

The Journal of Immunology

247

201

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A shift toward Th2 cytokine production has been demonstrated during pregnancy and high dose estrogen therapy and is thought to be the primary mechanism by which estrogen suppresses the development of experimental autoimmune encephalomyelitis. However, low dose estrogen treatment is equally protective in the absence of a significant shift in cytokine production. In this study cytokine-deficient mice were treated with estrogen to determine whether a shift in Th2 cytokine production was required for the protective effects of hormone therapy. Estrogen effectively suppressed the development of experimental autoimmune encephalomyelitis in IL-4 and IL-10 knockout mice and in wild type littermate mice with a similar potency of protection. Significant disease suppression was also seen in IFN-γ-deficient mice. The decrease in disease severity was accompanied by a concomitant reduction in the number of proinflammatory cytokine- and chemokine-producing cells in the CNS. Although there was no apparent increase in compensatory Th2 cytokine production in cytokine-deficient mice, there was a profound decrease in the frequency of TNF-α-producing cells in the CNS and the periphery. Therefore, we propose that one mechanism by which estrogen protects females from the development of cell-mediated autoimmunity is through a hormone-dependent regulation of TNF-α production.

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“…For example, mammalian mast cells, T and B cells and macrophages shows membrane AR and membrane ER (Benten et al, 1998(Benten et al, , 2001(Benten et al, , 2002Zaitsu et al, 2007). A membrane ER (Pang et al, 2008) and a membrane AR (review in Thomas et al, 2006) have recently been cloned and characterized in atlantic croaker, although nothing is known about membrane AR in fish immune tissues.…”

Section: Sex Steroid Hormones As Regulators Of the Immune Responsementioning

confidence: 99%

“…In the gilthead seabream, lymphocytes only express the ER gene (Liarte et al, 2011b). In mammals, however, B lymphocytes express both ER and ER genes, while there is debate as to whether or not T cells contain classical nuclear ER (Benten et al, 1998;Harkonen & Vaananen, 2006). In vitro functional assays demonstrated that 17-estradiol stimulates lymphocyte proliferation (Cook et al, 1994).…”

Section: Lymphocytesmentioning

confidence: 99%