Upstream eventInduction of GATA3 expression
Overproduction of IL-4
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
Th2 cells produce IL-4, IL-5, IL-10, and IL-13, meanwhile Th1 cells produce IL-12, TNF-α, and IFN-γ. During Th2 polarization, IL-4 produced by Th2 cell. IL-12 plays a central role in promoting the differentiation of naive CD4+ T cells into mature Th1 effector cells. Secretion of IL-10 from Th2 has been suggested to downregulate the DC-derived IL-12 production and lead to a Th2 differentiation (Aste-Amezaga M. 1998).
Evidence Supporting this KER
IFN-γ is noticeably reduced in pregnant women compared with non-pregnant women or in response to high levels of estrogen (Kruse et al. 2000). Thus, pharmacological or pregnancy levels of estrogen may skew the immune system from a Th1 to a Th2 profile (Ebru et al. 2011). Th2 differentiation is completely abolished both in vitro and in vivo when GATA3 is conditionally deleted in peripheral CD4 T cells from GATA-3-deficient (FF and FF cre) mice (Sung-Yun. 2004, Zhu J. 2004). Antigen-specific immune response is evaluated with lymphocyte from FF and FF cre mice injected with KLH, and cytokine production was measured by sandwich ELISA (Sung-Yun. 2004). Mouse lymphocytes stimulated with a massive amount of BPA (50 μM) were Th2 polarized, with prominent elevation of IL-4 as well as IL-10 (Lee MH. 2010). Similarly, BPA enhanced IL-4 production in antigen-activated T cells by ELISA or RT-PCR, although the concentrations of BPA that they utilized (10–50 μM) were high (Lee MH. 2003). In this experiment, IL-4 level is confirmed baseline when treated with anti-CD4 mAb. Exposure to BPA in adulthood mice promoted antigen-stimulated levels of IL-4, IL-10, and IL-13, but not IFN-γ (Huimin et al. 2008).
The proliferation of Stat6:ER Th1 cells was enhanced in a dose-dependent manner on days 10 and 31 after polarization by [3H]thymidine incorporation (the effective concentration of 4-HT was between 0.08 and 2 μM, and the toxic concentration was greater than 5 μM) (Kurata H. 1999, Zhu J. 2001).
Uncertainties and Inconsistencies
The essential transcription factors of Th2 are GATA-3 and STAT5. Activation of GATA-3 and STAT5 induce IL-4 production in naïve CD4 T cells. IL-4-mediated STAT6 activation promotes Th2 differentiation (Kaplan MH. 1996, Shimoda K. 1996, Takeda K. 1996).
Quantitative Understanding of the Linkage
When estrogen levels are low, T cell expansion shift toward a Th1 phenotype that produces IL-12, TNF-α, and IFN-γ. This response results in cellular immunity inducing inflammation and exacerbating cellular type autoimmune disease such as multiple sclerosis (MS) and EAE rather than SLE.
The effects of estrogen receptor signaling on T cells also appear to be dose dependent (Cunningham and Gilkeson, 2011). Treatment with low serum levels (60–100 pg/mL or 0.26–0.43 nM) of estradiol increased Th1 T-cell development in vitro by acting 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 dose levels (>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. (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).
IL-4 may serve multiple roles in the development of lupus: it may enhance autoantibody production via its direct B-cell effects, protect against autoimmunity via its T-cell suppressor effect, or perpetuate tissue damage via its direct effects on target organs (Ram Raj Singh 2003).
Known modulating factors
The Th1/Th2 shift is one of the most important immunologic changes during gestation. 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
- Aste-Amezaga M, Ma X, Sartori A, Trinchieri G. Molecular mechanisms of the induction of IL-12 and its inhibition by IL-10. J Immunol. 1998. 15;160(12):5936-44.
- Sung-Yun, Morgan L. T. I-Cheng H. (2004). GATA-3 deficiency abrogates the development and maintenance of T helper type 2 cells. Proceedings of the National Academy of Sciences. 101 (7): 1993-1998.
- Zhu J, Min B, Paul WE, et al. Conditional deletion of Gata3 shows its essential function in T(H)1-T(H)2 responses. Nat Immunol. 2004;5(11):1157-65.
- Melissa, C. and Gary, G (2011). Estrogen Receptors in Immunity and Autoimmunity. Clinical Reviews in Allergy & Immunology 40: 66-73.
- Lee, M. H., Chung, S. W., Kang, B. Y., Park, J., Lee, C. H., Hwang, S. Y. and Kim, T. S. (2003). Enhanced interleukin-4 production in CD4+ T cells and elevated immunoglobulin E levels in antigen-primed mice by bisphenol A and nonylphenol, endocrine disruptors: involvement of nuclear factor-AT and Ca2+. Immunology 109(1): 76-86.
- Huimin, Y., Masaya, T. and Kazuo, S. (2008). Exposure to Bisphenol A Prenatally or in Adulthood Promotes TH2 Cytokine Production Associated with Reduction of CD4+CD25+ Regulatory T Cells. Environmental Health Perspective 116(4): 514-519.
- Cunningham, M., Gilkeson, G., 2011. Estrogen receptors in immunity and autoimmunity. Clinical Reviews in Allergy and 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.
- 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.
- Kaplan MH, Schindler U, Smiley ST, Grusby MJ. Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity. 1996;4(3):313-9.
- Shimoda K, van Deursen J, Ihle JN, et al. Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature. 1996. 18;380(6575):630-3.
- Takeda K, Tanaka T, Akira S, et al. Essential role of Stat6 in IL-4 signalling. Nature. 1996. 18;380(6575):627-30.
- Zhu, J., Guo, L., Watson, C. J., Hu-Li, J. and Paul, W. E. (2001). STAT6 is necessary and sufficient for IL-4's role in Th2 differentiation and cell expansion. The Journal of Immunology 166(12): 7276-7281.
- Lee, J. and Lim K. T. (2010). Plant-originated glycoprotein (36kDa) suppresses interleukin-4 and -10 in bisphenol A-stimulated primary cultured mouse lymphocytes. Drug and Chemical Toxicology. 33(4): 421-429.
- Ram Raj Singh (2003). IL-4 and many roads to lupuslike autoimmunity. Clinical Immunology 108: 73–79