Oestrogen is a potent disease accelerator in SLE-prone MRL lpr/lpr mice

Carlsten, Hans; Tarkowski, Andrej; Holmdahl, Rikard; Nilsson, Lars‐Åke

doi:10.1111/j.1365-2249.1990.tb03311.x

Cited by 128 publications

(45 citation statements)

References 33 publications

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“…Previous reports suggested that E2 reduces pathological Th1 responses (20,33). Moreover, several studies reported that E2 administration accelerated disease activities in murine models of SLE (3,35,40), but inhibited experimental autoimmune encephalomyelitis, an animal model of MS (2). Autoreactive cells that escape immunosurveillance can result in many auto- immune diseases.…”

Section: Discussionmentioning

confidence: 99%

Physiologically high concentrations of 17β-estradiol enhance NF-κB activity in human T cells

Hirano¹,

Furutama²,

Hanafusa³

2007

American Journal of Physiology-Regulatory, Integrative and Comp

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trogen has diverse effects on inflammation and immune responses. That pregnancy is associated with remission of some autoimmune diseases and exacerbation of others suggests that physiological fluctuation in estrogen levels could affect the immune responses in humans. However, the molecular basis for these phenomena is poorly understood. We hypothesized that fluctuations of estrogen levels modulate intracellular signaling for immune responses via estrogen receptors (ERs). In reporter assays, 17␤-estradiol (E2) at a physiologically high concentration increased the activity of NF-B in Jurkat cells stimulated by PMA/ionomycin or TNF-␣. Overexpression and RNA interference experiments suggested that the effects were mediated through ER␤. Immunoprecipitation assay showed that both ER␣ and ER␤ are directly associated with NF-B in the cell nucleus. Using chromatin immunoprecipitation assay, we confirmed that ER␣ and ER␤ associated with NF-B and steroid hormone coactivators at the promoter region of NF-B regulated gene. Considering that NF-B regulates the expression of various genes essential for cell growth and death, estrogen could regulate the fate of T cells by affecting the activity of NF-B. To determine whether E2 alters the fate of T cells, we investigated E2 actions on T cell apoptosis, a well-known NF-Bmediated phenomenon. E2 increased apoptosis of Jurkat cells and decreased that of human peripheral blood T cells. Our results indicate that E2 at a physiologically high concentration modulates NF-B signaling in human T cells via ER␤ and affects T cell survival, suggesting that these actions may underlie the gender differences in autoimmune diseases. sex hormone; autoimmune disease; coactivator; transcription factor MANY AUTOIMMUNE DISEASES ARE more prevalent in women than in men (42, 44). Some autoimmune diseases, such as systemic lupus erythematosus (SLE), frequently show exacerbation during pregnancy (42), and in this regard, patients with SLE often have high serum estrogen concentrations (27). These clinical facts led us to hypothesize that fluctuation in estrogen levels could modulate autoimmune responses.Baseline estrogen concentrations do not differ significantly between men and women. However, the serum concentration of 17␤-estradiol (E2), the most potent and predominant estrogen in human serum, increases from baseline 10 pM to 40 nM during pregnancy (45). Estrogen has diverse effects on inflammatory and immune systems (8,33), and the physiological fluctuation in estrogen level could affect the immune responses in humans (5). However, the molecular basis for these phenomena is poorly understood.

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Section: Discussionmentioning

confidence: 99%

Physiologically high concentrations of 17β-estradiol enhance NF-κB activity in human T cells

Hirano¹,

Furutama²,

Hanafusa³

2007

American Journal of Physiology-Regulatory, Integrative and Comp

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“…SLE onset is most common in women of reproductive age, and the basis of this sex predisposition is not fully understood (11). The role of estrogen and of its receptors in the pathogenesis of SLE has been demonstrated by several previous studies (12)(13)(14)(15)(16). ER␣, rather than ER␤, plays a major role in regulating autoimmunity in (NZB ϫ NZW)F 1 mice, in a lupus-like syndrome develops spontaneously, by promoting the production of pathogenic autoantibodies (17).…”

mentioning

confidence: 94%

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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“…In lupus models in mice, the sustained increase in estradiol accelerates the start of the disease and shortens life [131,132]. Female SLE mice develop antibodies, lymphoadenopathies, arthritis, immunecomplex glomerulonephritis and die earlier than the equivalent males [133].…”

Section: Animal Model Studiesmentioning

confidence: 99%