Abstract
Dysregulation of cytokines is among the main abnormalities in Systemic Lupus Erythematosus (SLE). However, although, estrogens, which are known to be involved in lupus disease, influence cytokine production, the underlying molecular mechanisms remain poorly defined. Recent evidence demonstrates the presence of estrogen receptor in various cell types of the immune system, while divergent effects of estrogens on the cytokine regulation are thought to be implicated. In this paper, we provide an overview of the current knowledge as to how estrogen-induced modulation of cytokine production in SLE is mediated by the estrogen receptor while simultaneously clarifying various aspects of estrogen receptor signaling in this disease. The estrogen receptor subtypes, their structure, and the mode of action of estrogens by gene activation and via extranuclear effects are briefly presented. Results regarding the possible correlation between estrogen receptor gene polymorphisms and quantitative changes in the receptor protein to SLE pathology and cytokine production are reviewed.
Highlights
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown origin that affects several organ systems; diverse immunological abnormalities that are associated with this disease have been recognized both in human and in animal models with the most consistent being: (1) loss of B cell tolerance, (2) abnormal interactions between T and B cell signaling, (3) T, B cell and monocyte hyperactivity, (4) production of a wide range of pathogenic autoantibodies resulting from polyclonal B cell activation, and (5) defective clearance of autoantigens and immune complexes [1,2,3]
The key components of the immune system such as B and T lymphocytes, dendritic/macrophage cells, monocytes and thymus are involved in the underlying mechanisms of SLE, while an imbalance between Th-1 and Th-2 cytokine production plays a key role in the induction and development of the disease [4, 5]
Supporting the direct implication of estrogen in the development and the course of experimental murine SLE, Sthoeger et al [154] demonstrated therapeutic effects of tamoxifen, while three years later the same group [155] suggested that these beneficial effects were associated with cytokine modulations; treatment with tamoxifen restored the levels of IL-2, IL-4, IFN-γ, TNF-a, and IL-1 to the normal levels observed in control mice, implying an estrogen receptor-mediated effect
Summary
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown origin that affects several organ systems; diverse immunological abnormalities that are associated with this disease have been recognized both in human and in animal models with the most consistent being: (1) loss of B cell tolerance, (2) abnormal interactions between T and B cell signaling, (3) T, B cell and monocyte hyperactivity, (4) production of a wide range of pathogenic autoantibodies resulting from polyclonal B cell activation, and (5) defective clearance of autoantigens and immune complexes [1,2,3]. A switch from a type 1 (Th-1) to a type 2 (Th-2) T helper has been demonstrated where serum levels of Th-2 cytokines, such as interleukin IL4, IL-6, and IL-10, are elevated, while there is an observed decrease in production of Th-1 cytokines, including IL-2 and interferon IFN-γ [6, 7] Among these cytokines, IL-10 seems to play a central role in the pathogenesis of SLE as well as in disease flare induction [8,9,10], while IL-6 has been identified as being a potent contributor to the differentiation of Th0 to Th-2 cells [11], its production increasing in patients with active disease [12]. Oral contraceptive use was not associated with changes in the disease course in premenopausal women with SLE, at least in the nonactive phase, but hormone replacement therapy increased the risk of mild flares in postmenopausal patients [30]
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