Key Event Title
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|Binding to ER-α leading to exacerbation of SLE||KeyEvent|
|All life stages|
Key Event Description
Naïve CD4 T cells can differentiate into several different types of T helpers, and Th2 cells, capable of producing IL-4, IL-5 and IL-13, are involved in humoral immunity against extracellular pathogens and in the induction of asthma and other allergic diseases. It was reported that GATA-3 promotes Th2 responses through three different mechanisms (Zhu J. 2006). Cell fate determination in each lineage requires at least two types of transcription factors: the master regulators (GATA3) as well as the signal transducers and activator of transcription (STAT) proteins (Zhu J. 2010). A direct role in bridging distant regulatory elements has been demonstrated for GATA3 at Th2 cytokine loci (Spilianakis and Flavell, 2004). GATA3 is the Th2 master regulator (Zhu J．2010, Sung-Yun. 2004, Zhu J. 2004, Zheng W. 1997, Zhang DH. 1997), but it also plays important roles in multiple steps of CD4 T cell development (Ho IC. 2009). GATA3 can act as pioneer factors by initiating local chromatin opening and allowing the recruitment of other transcription factors to regulatory elements (Spilianakis and Flavell, 2004). Th2 differentiation is completely abolished both in vitro and in vivo when GATA3 is conditionally deleted in peripheral CD4 T cells (Zhu J. 2004, Pai SY. 2004). GATA-3 mRNA expression also increased in patients with SLE, compared with the healthy control groups (Zheng H. 2015, Sonia GR. 2012).
How It Is Measured or Detected
GATA3 mRNA in CD4 T cells can be detected by Real-time PCR (RT-PCR) (Lambert KC. 2005, Kurata H. 1999, Zhu J. 2001).
Domain of Applicability
Involvement of GATA3 in Th2 cell development through ER is common in humans, rodents, and other mammalian species (Ho IC. 2009). protein sequence conservation between all six vertebrate members (mouse, human, dog, cow, armadillo, capuchin and opossum) identifies GATA3 as having the highest sequence similarity with both its GATA paralogs and orthologs, suggesting that it may be closest to the ancestral mammalian GATA factor (Tremblay M. 2018).
Evidence for Perturbation by Stressor
Expression of GATA3 was induced in CD4+T cells treated with E2 at a concentration of 10-9 M (272.4 pg/mL) for 12-16 hours (Lambert KC. 2005). GATA3 expression has potential to induced IL-4 production in CD4+T cell. In contrast, expression of T-bet was decreased, which means E2 skew the immune system from a Th1 to a Th2 profile (Lambert KC. 2005).
GATA3 expression is induced in Th cells primed by dendritic cells exposed to BPA (Guo H. 2010). Purified naive T cells were cultured and expanded under Th1 culture conditions in the presence or absence of 0.3 μM 4-HT (Research Biochemicals Institute) for 2 weeks starting from days 1, 7, 14, or 21 (Kurata H. 1999).
- Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations. Annu Rev Immunol. 2010; 28:445-89.
- Spilianakis CG & Flavell RA, Long-range intrachromosomal interactions in the T helper type 2 cytokine locus. Nature Immunology. 2004; 5: 1017-1027.
- Zhu J, Paul WE. Peripheral CD4 T cell differentiation regulated by networks of cytokines and transcription factors. Immunol Rev. 2010; 238(1):247-62.
- 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.
- Zheng W, Flavell RA. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell. 1997. 16;89(4):587-96.
- Zhang DH, Cohn L, Ray P, Bottomly K, Ray A. Transcription factor GATA-3 is differentially expressed in murine Th1 and Th2 cells and controls Th2-specific expression of the interleukin-5 gene. J Biol Chem. 1997. 22;272(34):21597-603.
- Ho IC, Tai TS, Pai SY. GATA3 and the T-cell lineage: essential functions before and after Thelper-2-cell differentiation. Nat Rev Immunol. 2009;9(2):125-35.
- Zheng H, Guo X, Zhu Y, et al., Distinct role of Tim-3 in systemic lupus erythematosus and clear cell renal cell carcinoma. Int J Clin Exp Med 2015;8(5):7029-7038.
- Sonia GR, et al. Altered AKT1 and MAPK1 Gene Expression on Peripheral Blood Mononuclear Cells and Correlation with T-Helper-Transcription Factors in Systemic Lupus Erythematosus Patients. Mediators of Inflammation 2012, Article ID 495934
- Lambert KC, Curran EM, et al. Estrogen receptor alpha (ERalpha) deficiency in macrophages results in increased stimulation of CD4+ T cells while 17beta-estradiol acts through ERalpha to increase IL-4 and GATA-3 expression in CD4+ T cells independent of antigen presentation. J Immunol. 2005; 175(9): 5716-23.
- Kurata, H., Lee, H. J., O’Garra, A. and Arai, N. (1999). Ectopic expression of activated STAT6 induces the expression of Th2-specific cytokines and transcription factors in developing Th1 cells. Immunity 11: 677-688.
- 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.
- Tremblay M, GATA transcription factors in development and disease. 2018; 22:145(20).
- 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.