Upstream eventActivation of estrogen receptor
Induction of GATA3 expression
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Activation of estrogen receptor in immune cells leading to exacerbation of systemic lupus erythematosus||adjacent||Moderate||Moderate|
Life Stage Applicability
Key Event Relationship Description
Stressors bind to the ERs in immune cells, a ligand-activated transcription factor that regulates transcription of target genes in the nucleus or located in or adjacent to the plasma membrane (Deroo BJ. 2006). ERα is a nuclear hormone transcription factor that classically binds ligand stressors estrogen or EDC, further stabilizing dimers that subsequently bind estrogen response elements to transactivate or suppress specific target genes.
Evidence Supporting this KER
The GATA3 expression induced by TNF-α was enhanced in the presence of BPA. However, the T-bet expression did not change when tested at various culture conditions (Guo H. 2010, Uemura Y. 2008). Naive Th cells primed by BPA/TNF-α-matured DCs differentiated into Th2 cells with characteristically high IL-5/IFN-γ, IL-10/IFN-γ, and IL-13/IFN-γ ratios. However, the IFN-γ production was not affected at all, thus indicating that Th2 bias was induced by enhanced Th2 cytokine production (Guo H. 2010, Uemura Y. 2008). Also, dendritic cells exposed to BPA (100 nM) and TNF-α produced high levels of IL-10 relative to IL-12, and this induced Th2 deviation (Liu Y. 2009).
Uncertainties and Inconsistencies
Dendritic cells exposed to human exposure-relevant concentrations of BPA (10-100 nM) preferentially skewed T cells toward a Th2 phenotype. Th cells were primed by BPA/TNF-α-DCs. The administration of 17β-estradiol enhanced the differentiation of dendritic cells and increased IFN-γ production by dendritic cells in C57BL/6 mice.
Quantitative Understanding of the Linkage
When estrogen levels are low, T cell expansion shifts toward a Th1 phenotype that produces IL-12, TNF-α, and IFN-γ. This response results in cellular immunity inducing inflammation and exacerbating cellular autoimmune diseases such as multiple sclerosis (MS), rheumatoid arthritis (RA), and experimental autoimmune encephalomyelitis (EAE) rather than SLE.
The effects of estrogen receptor signaling on T cells also appear to be dose dependent (Melissa, and Gary 2011). Low serum levels (60–100 pg/mL or 0.26–0.43 nM) of estradiol have been shown to increase Th1 T-cell development in vitro through an ERα mediated mechanism (Maret et al. 2003). Treatment with low doses of estrogen (25 pg/ml or 0.1 nM) ameliorated disease, while high doses (>1000 pg/ml or 4.3 nM), which mimic pregnancy levels, prevented EAE onset and polarized T-cells to a Th2 phenotype in the EAE model (Bebo et al. 2001). High levels of estrogen during pregnancy have been reported to ameliorate T cell mediated diseases such as multiple sclerosis (Korn-Lubetzki et al. 1984).
Known modulating factors
The Th1/Th2 shift is one of the most important immunologic changes during the menstrual cycle and gestation. Immune activity shifts across the menstrual cycle, with higher follicular-phase Th1 cell activity and higher luteal-phase Th2 cell activity (Tierney et al. 2015). This is due to the progressive increase of estrogens, which reach peak level in the third trimester of pregnancy. At these high levels, estrogens suppress the Th1-mediated responses and stimulate Th2-mediated immunologic responses (Doria et al. 2006).
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
- Deroo BJ, Korach KS. Estrogen receptors and human disease. J Clin Invest. 2006 Mar;116(3):561-70.
- Guo H, Liu T, Ling F, et al. Bisphenol A in combination with TNF-alpha selectively induces Th2 cell-promoting dendritic cells in vitro with an estrogen-like activity. Cell Mol Immunol. 2010;7(3):227-34.
- Uemura Y, Liu TY, Narita Y, Suzuki M, Matsushita S. 17 Beta-estradiol (E2) plus tumor necrosis factor-alpha induces a distorted maturation of human monocyte derived dendritic cells and promotes their capacity to initiate T-helper 2 responses. Hum Immunol. 2008;69(3):149-57.
- Liu Y, Shi J, Ding B. Activation of peroxisome proliferator-activated receptor-gamma potentiates pro-inflammatory cytokine production, and adrenal and somatotropic changes of weaned pigs after Escherichia coli lipopolysaccharide challenge. Innate Immun. 2009;15(3):169-78.
- Kamogawa, Y., Lee, H.J., Johnston, J.A., McMahon, M., O’Garra, A., and Arai, N. (1998). Cutting Edge: A conditionally active form of STAT6 can mimic certain effects of IL-4. J. Immunol. 161, 1074–1077.
- Melissa, C. and Gary, G (2011). Estrogen Receptors in Immunity and Autoimmunity. Clinical Reviews in Allergy & Immunology 40: 66-73.
- Maret, A., Coudert, J. D., Garidou, L., Foucras, G., Gourdy, P., Krust, A., Dupont, S., Chambon, P., Druet, P., Bayard, F. and Guéry, J. C. (2003). Estradiol enhances primary antigen-specific CD4 T cell responses and Th1 development in vivo. Essential role of estrogen receptor α expression in hematopoietic cells. The European Journal of Immunology 33: 512-521.
- Bebo, B. F. Jr., Fyfe-Johnson, A., Adlard, K., Beam, A. G., Vandenbark, A. A.and Offner, H. Low-Dose Estrogen Therapy Ameliorates Experimental Autoimmune Encephalomyelitis in Two Different Inbred Mouse Strains. (2001). The Journal of Immunology. 166: 2080-2089
- Korn-Lubetzki, I., Kahana, E., Cooper, G. and Abramsky, O. (1984). Activity of multiple sclerosis during pregnancy and puerperium. Annals of Neurology 16(2): 229-231.
- Tierney, K. L., Julia, R. H. and Gregory, E. D. (2015). Sexual activity modulates shifts in Th1/Th2 cytokine profile across the menstrual cycle: An observational study. Fertility and Sterility 104 (6): 1513–1521.
- Doria, A., Iaccarino, L., Sarzi-Puttini, P., Ghirardello, A., Zampieri, S., Arienti, S., Cutolo, M. and Todesco, S. (2006). Estrogens in pregnancy and systemic lupus erythematosus. Annals of the New York Academy of Sciences 1069: 247-256.