Estrogen

Estrogens are steroid hormones synthesized from a cholesterol backbone and produced predominantly in the ovary in response to follicle-stimulating hormone (FSH); 17p-estradiol is the most abundant estrogenic compound in the circulation. Metabolic precursors of estrogen include progesterone, dehydroepiandrosterone, and testosterone. Some catabolites of 17p-estradiol such as 16-hydroxyestrone display high estrogenic activity. Many SLE patients have high levels of 16-hydroxyestrone and low levels of androgen [8]. Among the many effects of estrogen is increased prolactin secretion.

Two types of estrogen receptor, estrogen receptor a (ERa) and estrogen receptor p (ERp) mediate the effects of estrogen. They are expressed not only in reproductive tissues but also in multiple other cell types, including cells of the immune system, such as monocytes and macrophages [40], NK cells [41], B and T lymphocytes [34] [42]. These receptors are targets for both endogenous and exogenous estrogens and for pharmacological estrogen receptor modulators. The classic signaling pathway for estrogen is ligand-dependent receptor activation with activated estrogen receptors acting as transcription factors [43]. There are differences in the structure and cellular distribution of ERa and p that suggest different biological roles for the two receptors. In addition, there appears to be membrane-associated estrogen receptors, which are expressed by T lymphocytes [44] and macrophages [45] but not B lymphocytes [46]. These receptors are involved in nongenomic rapid responses to estrogen. It is not clear whether these receptors are an alternative splice variant of ERa/p [47] or the recently described membrane G-protein-coupled estrogen receptor GPR30 [48].

Estrogens affect both B and T lymphopoiesis. B cell development in the bone marrow is inhibited by 17p-estradiol and during pregnancy B cell lymphopoiesis is reduced [49]. In estrogen-treated mice, lymphoid-restricted progenitors are selectively depleted [50]. Estrogen induces thymic atrophy with a reduction of T cell lymphopoiesis; this atrophy is mainly attributable to the effects ofERa engagement. While all T cell subsets are reduced, there is a disproportionate loss of CD4+CD8+ double-positive cells [51]. The CD4+ to CD8+ T cell ratio is altered with an increase of CD8+ T cells [52]. Furthermore, a reversible thymic atrophy is observed during pregnancy.

It has been reported that pregnancy is associated with a bias toward the production of Th2 cytokines by T cells. C57Bl/6 mice are usually resistant to Leishmania infection due to a strong Th1 response, but during pregnancy female C57BL/6 mice become susceptible to Leishmania. This susceptibility correlates with a switch from a Th1 to a Th2 pattern of cytokine secretion by splenocytes with decreased secretion of IFNy and increased secretion of IL4, IL5, and IL10 [53]. While a shift to a Th2 bias has been attributed to estrogen, estrogen can also enhance a Th1 response. The IFNy promoter possesses an estrogen response element that allows estrogen to directly stimulate IFNy secretion through a mechanism that requires ERa expression in hematopoietic cells [54, 55].

Estrogen also affects monocyte differentiation. Estrogen treatment increases FasL expression in the human monocytic cell line U937 through estrogen response elements present in the FasL promoter [40]. Estrogen also induces apoptosis in monocytes, which is dependent on ERp engagement. In addition, 17p-estradiol increases TNFa synthesis and decreases IL-10 synthesis in PMA-differentiated U937 cells [56]. Tamoxifen, a pure ERp antagonist and partial ERa agonist, and ICI-182,780, an antagonist of both ERa and p, completely abolish induction of TNFa [56]. In contrast, transcription and protein synthesis of CD16 (FcyRIII), an activation receptor, are significantly increased in the absence of estrogen. In estrogen-deprived macrophages, the higher level of CD16, is responsible upon cross-linking for the secretion of significantly more TNFa, IL-1p, and IL-6 [57]. Thus, the cytokine profile induced by the presence or absence of estrogen is complex and dependent on the combination of activating factors.

To determine the action of estrogen on autoimmune pathologies, several studies have been performed with peripheral blood mononuclear cells (PBMCs) from healthy donors and SLE patients. PBMCs of healthy donors stimulated in vitro with pokeweed mitogen and treated with 17p-estradiol show enhanced immunoglobulin secretion. This increase in immunoglobu-lin production is dose-dependant for concentrations of 17p-estradiol ranging from 10-10 to 10-8 M (eq 0.03-3 ng/ml), and is also observed in PBMCs of

SLE patients with an accompanying enhancement of anti-dsDNA IgG production [58]. Treatment of PBMCs from SLE patients with 170-estradiol at 10-8M also causes a decrease in both apoptosis and TNFa production and an increase in IL-10 production, mostly due to estrogen's effects on monocytes [59]. This is in contrast to the effect of estrogen on PBMCs of healthy donors.

As highlighted in Table 1, data obtained with mouse models of SLE display a strong link between response to estrogen and a female bias in disease susceptibility and conversely the absence of response to estrogen in the absence of female susceptibility [60-67].

The studies with MRL/lpr mice illustrate an estrogen paradox that also appears to exist in human disease [68]. In experimental autoimmune en-cephalomyelitis (EAE), estrogen ameliorates disease manifestations, while in lupus estrogen worsens disease. In human disease, estrogen ameliorates rheumatoid arthritis while potentially leading to exacerbations in SLE. This may reflect the fact that estrogen alters not only the induction of autoreactivity, but also effector mechanisms of target organ injury.

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