Molecular Mechanisms Involved in the Estrogen-Dependent Regulation of Calcineurin in Systemic Lupus Erythematosus T Cells

doi:10.1006/clim.2000.4844

Clinical Immunology

Volume 95, Issue 2, May 2000, Pages 124-134

https://doi.org/10.1006/clim.2000.4844 Get rights and content

Abstract

Previous experiments in our laboratory indicated that calcineurin expression and PP2B phosphatase activity increased when estrogen was cultured with SLE T cells but not with T cells from normal women. In this report we extended our findings to show that estrogen receptor (ER) antagonism by ICI 182,780 inhibited the estrogen-dependent increase in calcineurin mRNA and phosphatase PP2B activity indicating that estrogen action was mediated through the ER. Inhibition of de novo protein synthesis with cycloheximide suggested that the estrogen-dependent increase in T cell calcineurin mRNA was a direct effect of the ER and new protein synthesis was not required. Estrogen increased calcineurin mRNA in systemic lupus erythematosus (SLE) T cells at 6 h after the start of culture correlating with increased phosphatase activity at this same time. Phosphatase activity increased significantly (P < 0.02) in lupus T cells cultured for 8 h in estradiol-containing medium. Reverse transcription and polymerase chain amplification revealed that ER-β and ER-α were expressed in female and male T cells from SLE patients and normal controls. However, calcineurin steady-state mRNA levels were unaffected by estradiol in cultured T cells from male SLE patients and normal male and female controls. These data indicate that estrogen, bound to the ER, evokes a direct increase in calcineurin expression in T cells from female lupus patients. This gender-specific response suggests that ER function is altered in women with the female predominant autoimmune disease, SLE.

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Our findings on calcineurin also can not be discussed without the effects of estrogen and GCS. It was known that estrogen treatment directly increased the expression of calcineurin (CN) in T cells from lupus patients at mRNA level [41]. We published two articles on CN.
The physiological role of protein kinase C (PKC) enzymes in the immune system is presented briefly. From earlier publications of others data were collected how the defects of one/two isoenzymes of PKC system suggested their involvement in the pathogenesis of human autoimmune diseases. Our observations on the defects of seven PKC isoenzymes in the peripheral blood mononuclear cells (PBMC) demonstrate that these molecular impairments are not prerequisits of the pathogenesis of systemic lupus erythematosus (SLE), mixed connective tissue disease and Sjögren's syndrome. However, these defects can modulate the disease activity and symptoms especially in SLE by several pathways. The role of PKC system in other forms of autoimmune diseases is also very small. It was of note that we detected decreased expression of PKC isoenzymes in PBMC of a European white family with an X-linked genetic background showing seasonal undulations in the lupus patient and also in her healthy mother.
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Autoimmune diseases are typically associated with an increased risk of cardiovascular disease. Most diseases of autoimmune origin typically present with increased prevalence toward one sex, for example, Systemic Lupus Erythematosus (SLE) is nine times more prevalent in women than men. Sex hormones and chromosomes have been implicated in the pathogenesis and course of autoimmune diseases, and may likewise influence cardiovascular disease associated with autoimmune disease. This chapter explores theories of autoimmunity and how these theories relate to sex, details concerning how SLE typically presents throughout the female lifespan, and then concludes with a summary of cardiovascular sequelae associated with SLE and other autoimmune diseases. Ultimately, SLE is notorious among autoimmune diseases for its overwhelming skew toward females, its wide range of systemic morbidities, disease flares that occur in conjunction with pregnancy, and the unusually high prevalence of hypertension in reproductive-age women, who are normally protected from cardiovascular disease.
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Autoimmune diseases result from a complex interaction of genetics, environment, and hormones, eventually leading to a break in immune tolerance to “self”-causing pathology and destruction of various tissues. Diseases may be organ specific, affecting mainly the joints (rheumatoid arthritis) or neuronal tissue (multiple sclerosis), or may be systemic, including systemic lupus erythematosus (SLE), Sjögren syndrome and dermatomyositis. SLE is a multi-system autoimmune disease that mainly affects women of child-bearing age with significant morbidity, and it can affect any organ in the body, including the skin, joints, and kidneys.¹ T lymphocytes are major effectors of the adaptive immune system and are crucial in host defence against pathogens. Aberrant T cells play a critical role in autoimmune disease, not only by helping B cells to enable autoantibody production but also by infiltrating tissues leading to immunopathology. In this chapter we describe the role and regulation of T cell signalling, activation, gene expression, and cytokines with a focus on T cell defects in SLE, the prototype autoimmune disease.
Demethylation within the proximal promoter region of human estrogen receptor alpha gene correlates with its enhanced expression: Implications for female bias in lupus
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Systemic lupus erythematosus (SLE) is a systemic autoimmune disease primarily affecting women. Previous studies have indicated that sex hormone estrogens contribute to the female predilection of SLE. Estrogen regulates gene expression by translocating estrogen receptors (ER) α and β into the nucleus where they induce transcription by binding to estrogen response elements of target genes. We have previously observed that expression of ERα gene and protein in lupus patients is significantly higher than in healthy controls and that estradiol up-regulates calcineurin expression via over-expression of ERα gene in SLE. However, the pathogenesis of over-expression of ERα gene is unknown. Here we report that enhanced expression of ERα mRNA and protein in SLE and rheumatoid arthritis is associated with DNA demethylation within the proximal promoter region located between −232 and +81 base pair relative to transcription start site of human ERα gene (GenBank Accession no. AL356311.6). The frequency of DNA demethylation was comparable between male and female. These findings suggest that estrogen and demethylated ERα promoter associated up-regulated ERα genes are two critical factors in the gender biased development of autoimmune diseases besides genetic factor.
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Such intrinsic activation status of SS-SGEC has been invoked to explain the significantly increased constitutive expression of various immuno-active molecules [1], as well as the significant sensitivity to TLR3-mediated apoptosis [27] that is observed in cultured SGEC lines derived from SS patients. In fact, the disease activity status has been shown to differentially affect the estrogenic responses of T cells derived from SLE patients (Table 1 [28–32]), as well as of dendritic cells of experimental animals with lupus-like disorder [33]. In the same context, the differentiation state has been also shown to influence the responsiveness of monocytes and B cells to estrogens [34,35].
Several lines of evidence indicate that salivary gland epithelial cells (SGEC) play an important role in the pathogenesis of primary Sjogren’s syndrome (SS). Normal SGEC have been shown to possess functional estrogen receptors, however, the estrogenic response of SGEC in patients with SS has not been previously assessed. To address this issue, we comparatively tested cultured non-neoplastic SGEC lines from SS patients (SS-SGEC, n = 8) and from disease controls (control-SGEC, n = 12) in a standard estrogenic inhibition assay of cytokine-induced adhesion molecule expression, where the modulation of the expression of constitutive and interferon-gamma (IFNγ)-induced CD54/ICAM.1 molecules following treatment with 17β-estradiol (E2) was evaluated by flow cytometry. Similarly high ICAM.1 expression was induced by IFNγ in control-SGEC and SS-SGEC lines. E2-treatment did not modify the constitutive ICAM.1 expression in either control-SGEC or SS-SGEC lines. In line with previous results, E2-pretreatment of control-SGEC was found to impede significantly the IFNγ-induced upregulation of ICAM.1 (p = 0.003). However, such inhibition was not observed in the SS-SGEC lines (p = 0.55). Such aberrant response of SS-SGEC to estrogens did not appear to associate with altered expression of estrogen receptor (ER) proteins, as no discernible differences could be revealed by immunoblotting and immunohistochemistry in the patterns or the intensity of ERα and ERβ (ERβ1- and ERβ2-isoforms) protein expression in SGEC lines or minor salivary gland tissues between SS patients and disease controls. The deficient estrogenic responsiveness of SS-SGEC likely represents a manifestation of the intrinsic epithelial activation that characterizes SS and possibly indicates the perturbation of the immunoregulatory potential of estrogens in SS-epithelia.

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^☆: This research was supported in part by grants from the Sarah Morrison fund, the Evans Endowment, and St. Luke's Foundation.

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Regular ArticleMolecular Mechanisms Involved in the Estrogen-Dependent Regulation of Calcineurin in Systemic Lupus Erythematosus T Cells☆

Abstract

Immunol. Today

Life Sci.

J. Allergy Clin. Immunol.

Clin. Immunol. Immunopathol.

J. Biol. Chem.

Clin. Immunol. Immunopathol.

Anal. Biochem.

Biochem. Biophys. Res. Commun.

FEBS Lett.

J. Biol. Chem.

Immune cell biochemical abnormalities in systemic lupus erythematosus

Clin. Exp. Rheumatol.

Immune cell signaling aberrations in human lupus

Immunol. Res.

Hormonal modulation in SLE

Arthritis Rheum.

Effect of pregnancy on course of systemic lupus erythematosus

J. Am. Med. Assoc.

Oral contraceptives and systemic lupus erythematosus

Arthritis Rheum.

Oral contraceptives and systemic lupus erythematosus

Arthritis Rheum.

Gonadal steroids and immunity

Endocr. Rev.

The role of sex hormones in systemic lupus erythematosus

Curr. Opin. Rheumatol.

Human estrogen receptor β-gene structure, chromosomal localization and expression pattern

J. Clin. Endocrinol. Metab.

Oestrogen receptors—An overview

J. Intern. Med.

Survival of reproductive behaviors in estrogen receptor β gene-deficient (βERKO) male and female mice

Proc. Natl. Acad. Sci. USA

Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene

Proc. Natl. Acad. Sci. USA

Steroid receptor family: Structure and functions

Endocr. Rev.

Phosphorylation of human estrogen receptor alpha by protein kinase A regulates dimerization

Mol. Cell. Biol.

High prevalence of T cell type I protein kinase A deficiency in systemic lupus erythematosus

Arthritis Rheum.

Presence of estrogen binding sites on macrophage-like synoviocytes and CD8+ CD29+ CD45RO+ T lymphocytes in normal and rheumatoid synovium

Arthritis Rheum.

Presence of oestrogen receptors in human blood mononuclear cells and thymocytes

Acta. Endocrinol.

Peripheral blood T cells and monocytes, and B cell lines derived from lupus patients express estrogen receptor transcripts similar to those of normal controls

J. Rheumatol.

Regular Article
Molecular Mechanisms Involved in the Estrogen-Dependent Regulation of Calcineurin in Systemic Lupus Erythematosus T Cells☆