Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Estrogen can modulate autoimmunity in certain models of systemic lupus erythematosus. Recently, we have shown that it can mediate survival and activation of anti-DNA B cells in a mouse transgenic for the heavy chain of a pathogenic anti-DNA antibody. To identify whether estrogen effects reflect increased prolactin secretion, we characterized B-cell autoreactivity in transgenic mice given both bromocriptine (an inhibitor of prolactin secretion) and estradiol. Treatment of mice with estradiol plus bromocriptine led to reduced titers of anti-DNA antibodies and diminished IgG deposition in kidneys compared with treatment with estradiol alone. However, mice treated with estradiol plus bromocriptine showed an expansion of transgene-expressing B cells and enhanced Bcl-2 expression, similar to those of estradiol-treated mice. We identified anergic high-affinity anti-DNA B cells in mice treated with estradiol plus bromocriptine, and we showed by molecular analysis of anti-DNA hybridomas that their B cells derive from a naive repertoire. Thus, the estradiol-induced breakdown in B-cell tolerance can be abrogated by bromocriptine, which induces anergy in the high-affinity DNA-reactive B cells. These studies demonstrate that some of the effects of estrogen on naive autoreactive B cells require the presence of prolactin and, thus, suggest potential therapeutic interventions in lupus.
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PMID:Bromocriptine restores tolerance in estrogen-treated mice. 1110 90

Systemic lupus erythematosus (SLE) is an autoimmune disease that occurs primarily in women (9:1 compared to men). Estrogen is a female sex hormone that acts on target cells through specific receptor proteins and alters the rate of transcription of target genes. Experiments in our laboratory have shown that calcineurin steady-state mRNA levels and phosphatase activity increase when estrogen is cultured with SLE T cells. This estrogen-dependent increase is dose-dependent, hormone-specific and temporally regulated. Estrogen receptor antagonism by ICI 182,780 inhibits the increase in calcineurin mRNA and phosphatase activity, while cycloheximide has no effect suggesting that new protein synthesis is not required. Reverse transcription and polymerase chain amplification indicate that estrogen receptor-alpha and estrogen-beta are expressed in human T cells. However, calcineurin does not respond to estrogen stimulation in T cells from normal females, males and lupus males. Taken together, these results indicate a differential function of the estrogen receptor in women with lupus. A model is proposed that suggests estrogen, acting through the estrogen receptor, enhances T cell activation in women with lupus resulting in amplified T-B cells interactions, B cell activation and autoantibody production.
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PMID:Gender differences in autoimmunity: molecular basis for estrogen effects in systemic lupus erythematosus. 1140 98

Estrogen and prolactin have a reciprocal endocrinologic relationship and both hormones have pleiotropic effects on the immune system. Despite the presence of a number of confounding variables, these hormones modulate autoimmunity; however, mechanisms by which this modulation occurs remain obscure. Estrogen appears to suppress cell-mediated and augment humoral-based immunity. Prolactin appears to stimulate both cell and humoral-based immunity. Both hormones have been shown to modulate IFN gamma secretion. Similar evidence in experimental models, human autoimmune disease, and during pregnancy in autoimmune disease patients suggests disparate effects of estrogen and prolactin on autoimmune responses and disease pathogenesis. In the NZB x NZW F1 mouse model of lupus, prolactin accelerates disease expression, whereas estrogen, devoid of its prolactin stimulating properties, is immunosuppressive and inhibits IL-2 production. Estrogen, because of its endocrinologic and immune effects, may directly or indirectly stimulate or inhibit immune responses. These dichotomous effects have limited its successful pharmacologic manipulation in human autoimmune disease with estrogen compounds, tamoxifen, oral contraceptives, antigonadotropic agents, or ovulation induction regimens. In contrast, reduction of immunostimulatory concentrations of prolactin with bromocriptine has successfully suppressed development or expression of murine and human autoimmune disease. Further investigation into actions and interactions of estrogen and prolactin with autoimmunity will provide a better understanding of the female preponderance of autoimmunity and facilitate a more rational approach to hormonal immunotherapy.
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PMID:Estrogen, prolactin, and autoimmunity: actions and interactions. 1140 18

Estrogen metabolism in women with SLE is weighted towards 16alpha-hydroxyestrone, an estrogenic compound that might fuel disease activity. Indole-3-carbinol (I3C) is a nutritional compound that can shift estrogen metabolism towards less estrogenic metabolites. However, the effects of I3C in women with SLE have not been studied. Open-label 1-week metabolic study of 375 mg/day I3C was carried out in women with SLE, followed by a 3-month observational period for disease activity. The primary outcome measure was the change in ratio of urinary 2:16alpha hydroxyestrone levels. Secondary measures included the SLE Disease Activity Index. Seventeen clinically premenopausal women fulfilling ACR criteria for probable/definite SLE (mean age 37.9 y, range 20-49 y, mean disease duration 4.3 y, range 0.5-15) completed the 1-week metabolic study; 12 took I3C for 3 months. The mean 2:16alpha hydroxyestrone ratio increased by 1.84 to 3.15 (P = 0.0001). Mean SLEDAI scores were 10.0 (baseline); 6.25 (3 months); and 8.8 (3 months after withdrawal; P = NS). Women with SLE can manifest a metabolic response to I3C and might benefit from its antiestrogenic effects. We did not observe any striking effects on SLE disease activity during the 3-month observational period.
Lupus 2001
PMID:Indole-3-carbinol in women with SLE: effect on estrogen metabolism and disease activity. 1178 85

Estrogen is believed to contribute to the development of the autoimmune disorder systemic lupus erythematosus (SLE) (lupus) in women. We hypothesized that estrogen might promote the development of lupus by altering apoptosis of bone marrow cells, perhaps through regulation of the apoptotic proteins Bax and Bcl-2. We compared the effects of estrogen (E2) and thrombopoietin (TPO) on the expression of Bax or Bcl-2 in bone marrow cells isolated from female non-lupus (NZW or NZB parental strains) or lupus-prone (NZB and NZW cross; NZB/W) mice. We report that the basal level of Bax in parental bone marrow cells was significantly greater than that of cells from NZB/W animals. Treatment of NZB or NZW marrow cells with E2 resulted in a significant decrease in Bax expression, which was completely reversed upon co-treatment with TPO. Bax expression was not significantly altered by E2 and/or TPO in NZB/W cells. Bcl-2 levels did not differ between murine strains under basal or hormone-treated conditions. Lower basal expression of Bax protein was associated with significantly less apoptosis for NZB/W marrow cells. In addition, there were significantly greater numbers of cells in bone marrow of lupus-susceptible animals. Our results indicate that bone marrow cells of NZB/W animals differ physiologically from those of NZW or NZB mice, and suggest that decreased expression of Bax in bone marrow precursors may lead to decreased apoptosis of mature blood cells in lupus-susceptible mice.
Lupus 2001
PMID:Altered Bax expression and decreased apoptosis in bone marrow cells of lupus-susceptible NZB/W mice. 1178 88

Oral contraceptives (OCs) can affect the skin through their hormonal effects or through iatrogenic effects associated with their toxicity in certain individuals. They may also be beneficial in certain androgen-dependent dermatoses. Toxic effects of OCs are rare but potentially serious; they should be diagnosed early and require permanent termination of OC use. The clinical manifestations are variable and not specific to the medication. The most frequently reported manifestations are allergic vascularities which may lead to serious renal complications, fixed pigmented erythema, urticaria, which may have other etiologic factors, and lichenoid eruptions. Combined OCs, because of their estrogen content, may cause sensitivity to light in susceptible women. Other dermatoses can be initiated or aggravated by OCs without direct relation to their hormonal effects. OCs are therefore contraindicated if there is a personal or family history of porphyries or a personal history of systemic lupus erythematosus, erythema nouex, herpes gestationis, or malignant melanoma. Hormonal-related dermatological effects caused by either progestins or estrogens have become less frequent as dose levels have declined. Chloasma, either melasma or a poorly defined spotty pigmentation, accounts for 2/3 of cases of OC-related dermatoses. It is more common in women of Mediterranean background. 80% of affected OC users have a history of "mask of pregnancy", but the condition is also found in nulliparas. Exposure to sunlight is a factor. Women with a history of chloasma of pregnancy and dark coloring should not use OCs. Seborrhea is directly related to the androgen effect of OCs and is less likely to occur with 17 OH progesterone derivatives than with 19 norsteroid derivatives. The role of androgens in acne is well known, but 2 other factors are necessary: an anomaly in keratinization and proliferation of corynebacterium acnes, a saprophyte of the follicles. OCs do not necessarily need to be suspended during well-conducted acne treatment. Alopecia is rare but difficult to diagnose because of its psychological aspects. Androgenic alopecia is aggravated by progestins derived from 19 norsteroids. True hirsutism caused by an androgen-producing ovarian pathology is not related to OC use. Estrogens are incriminated in the etiology of telangiectasies, permanent dilatations of the arterioles. Once developed the condition does not regress and requires treatment with sclerosing agents, electrocoagulation, or laser. The various dermatological risk factors should be ruled out before prescription of an OC. Classic contraceptive pills are not commonly used in treatment of common acne because the strongly estrogenic climate required for therapeutic utility carries the risk of hypertriglyceridemia, thrombophlebitis, and possibly carcinogenesis. The recent development of pills containing the antiandrogen cyproterone acetate instead of a progestin in combination with ethinyl estradiol reduces androgenic effects in women. This pill may be useful in cases of severe acne, severe seborrhea, androgenic alopecia, or excessive facial hair.
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PMID:[Cutaneous effects in hormonal contraception]. 1228 Dec 76

The cause or mechanism of the female predisposition in systemic lupus erythematosus and progressive systemic sclerosis is largely unknown. Accumulating evidence shows that dysfunction or activation of endothelial cells plays an important role in these conditions. In this study, we investigated the influence of various steroid hormones on the IL-1beta (50 U/mL)/TNF-alpha (50 U/mL) stimulated human dermal microvascular endothelial cell line (HMEC-1) and human umbilical vein endothelial cells (HUVEC). Dexamethasone showed significant inhibition of cytokine-induced ICAM-1 expression in HMEC-1, and E-selectin, VCAM-1 and ICAM-1 expressions in HUVEC. Androgens, especially dihydrotestosterone had a small, but statistically significant suppressive effect in HMEC-1 only. Estrogen exhibited no regulatory function in either cell line. No obvious expression of estrogen and androgen receptors could be demonstrated in either cell by immunostaining. Our study provided some pharmacological evidence that the superior anti-inflammatory effect of glucocorticoids on vasculitis was partly due to their inhibition of the CAM expression in endothelial cells. More studies are needed to determine if androgens could have a protective effect in vasculitis or vasculopathy associated with connective tissue diseases.
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PMID:Effects of dexamethasone and sex hormones on cytokine-induced cellular adhesion molecule expression in human endothelial cells. 1237 Jan 31

Estrogen's role in the sex differences observed in autoimmune diseases such as systemic lupus, multiple sclerosis, and rheumatoid arthritis have remained unclear. Complicating the understanding of the immunomodulatory effects of estrogen are (1) the effects of estrogen on multiple components of the immune response; (2) its varied effects on different systems in which it appears pro-autoimmune, as in murine lupus, or anti-inflammatory, as in EAE; and (3) its effects on other hormones which are potentially immunomodulatory. Recent reports have shed light on the role of estrogen in the modulation of lymphocyte survival and expansion and in the elaboration of Th1 versus Th2 cytokines and on the mechanisms by which estrogen can activate via multiple signaling and genomic pathways in immune cells.
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PMID:Estrogen as an immunomodulator. 1550 85

Estrogen treatment has been shown not only to exacerbate disease activity and accelerate death in spontaneous murine models of lupus but also to induce a lupus-like phenotype in non-spontaneously autoimmune mice. In mice transgenic for the H chain of an anti-DNA Ab, estrogen rescues naive autoreactive B cells that normally are deleted and causes them to mature to a marginal zone phenotype. Estrogen further leads to the activation of this population causing an elevation of serum anti-DNA Ab titers and renal disease. This study was designed to evaluate the therapeutic potential of tamoxifen, a selective estrogen receptor modulator, on estrogen-induced lupus. Mice treated with both estradiol and tamoxifen showed no elevation in anti-DNA Ab titers and consequently no glomerular IgG. The DNA-reactive B cell population that is rescued by estrogen was present in an anergic state in mice treated with both estradiol and tamoxifen. Estradiol enhances transitional B cell resistance to apoptosis and expands the population of marginal zone B cells; tamoxifen did not impede the enhanced resistance to apoptosis, but prevented the development of autoreactive cells as marginal zone B cells. Thus, estrogen-induced autoimmunity proceeds through two distinct molecular pathways, one affecting survival and the other maturation. Activation, but not survival, of autoreactive B cells can be abrogated by tamoxifen. Drugs that modulate even some of the effects of estrogen may be beneficial in patients with lupus. Eventually, understanding the pathways involved in survival and activation of autoreactive B cells will permit the development of therapeutics that target all relevant pathways.
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PMID:Tamoxifen blocks estrogen-induced B cell maturation but not survival. 1603 77

The role of exogenous estrogen in the initiation and maintenance of human systemic lupus erythematosus (SLE) remains very controversial. To review the current literature of the safety of using exogenous estrogens in patients with SLE, a Medline search for articles published between 1970 et 2004 regarding this relationship was performed. Although cohort studies suggest an increase in the incidence of SLE with both oral contraceptives and hormone replacement therapy, recent retrospective studies suggest that the risk of flares is not increased with hormone replacement therapy. Large prospective double blind placebo controlled studies inclusive of all ethnic groups such as the Safety of Estrogen in Lupus Erythematosus National Assessment (SELENA) trial had to provide the basis for definitive recommendations but it had been interrupted after WHI study results.
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PMID:[Estrogen use in systemic lupus erythematosus]. 1613 52


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