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

Abstract

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.

Role of Nicotinic and Estrogen Signaling during Experimental Acute and Chronic Bladder Inflammation

“…27 Physiologically high concentrations of 17␤-estradiol modulate NF-B signaling in human T cells. 28 In this study we found that NF-B is activated during chronic bladder inflammation induced by cyclophosphamide or furthered by cyclophosphamide and mecamylamine together. However, the additional treatment with estrogen and/or anabasine resulted in the translocation of p65 to the cytoplasm, suggesting decreased NF-B activity.…”

Estrogen augments the T cell-dependent but not the T-independent immune response

“…Cellular signaling mechanisms activate the translocation of NFjB from cytoplasm to nucleus, which is required for NFjB to become a transcriptional regulator. Differential regulation of NFjB proteins by estrogen in spleen cells and in human T cells was recently reported [32,33]. We have tested whether in vitro treatment with bE2 can modulate subcellular distribution of NFjB in separated murine B and T lymphocytes by confocal laser scanning microscopy.…”

LPS induces GROα chemokine production via NF-κB in oral fibroblasts

“…17b-estradiol, has no effect on LPS-induced GROa gene activity in human PDL cells, suggesting that estrogen has no antiinflammatory effect via this mechanism. In order to detect any possible effect of estrogen we used a physiologically high concentration (100 nM) of 17b-estradiol, which is about the same concentration observed in plasma during pregnancy [24,25].…”