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Relationship: 2021

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Induction of GATA3 expression leads to Increase of Th2 cells producing IL-4

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Induction of GATA3 expression

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Increase of Th2 cells producing IL-4

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Binding to estrogen receptor (ER)-α in immune cells leading to exacerbation of systemic lupus erythematosus (SLE)	adjacent	Moderate	Moderate	Yasuharu Otsubo (send email)	Under development: Not open for comment. Do not cite	Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Intrachromosomal interactions in the Th2 cytokine locus may form the basis for the coordinated transcriptional regulation of cytokine-encoding genes by the Th2 locus control region (Spilianakis and Flavell, 2004). During Th2 cell differentiation, binding patterns of PcG and TrxG proteins are dynamically changed at the Gata3 gene locus, and these epigenetic changes result in GATA3 protein upregulation, which consequently induces chromatin remodeling at the Th2 cytokine gene loci, including Il4, Il5, and Il13 (Ansel KM. 2006, Horiuchi S. 2011).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

Th2 differentiation is completely abolished both in vitro and in vivo when GATA3 is conditionally deleted in peripheral CD4 T cells. Th2 cells from both knockout animals showed reduction in IL-4 production. (Zhu J. 2004, Pai SY. 2004).

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). IL-4 may serve multiple roles in the development of lupus: it may enhance autoantibody production via its direct B-cell effects (Ram RS. 2003).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

The proliferation of Stat6:ER Th2 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). Purified naive T cells were activated and infected with RV-Stat6:ER. The cells were cultured and expanded under Th 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 and the cells were analyzed for cytokine (IL-4) expression by flow cytometer analysis of intracellular cytokine production or cytokine ELISA (Kurata H. 1999, Zhu J. 2001). CD4 T cells from Stat6-knockout mice are not able to drive Th2 differentiation and cell expansion under null Th cell (ThN) conditions with added with IL-4 (Zhu J. 2001).

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).

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

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).

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

The effects of estrogen receptor signaling on T cells also appear to be dose dependent (Cunningham M. 2011). When estrogen levels are low, T cell expansion shift toward a Th1 phenotype that produces IL-12, TNF-α, and IFN-γ.

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

MIE:

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KE XX:

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Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

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Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

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Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

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References

List of the literature that was cited for this KER description. More help

Spilianakis CG & Flavell RA, Long-range intrachromosomal interactions in the T helper type 2 cytokine locus. Nature Immunology. 2004; 5: 1017-1027.
Ansel KM, Djuretic I, Tanasa B, RaoA. 2006. Regulation ofTh2 differentiation and Il4 locus accessibility. Annu. Rev. Immunol. 24:607-56.
Horiuchi S, Onodera A, Hosokawa H, Watanabe Y, Tanaka T, et al. 2011. Genome-wide analysis reveals unique regulation of transcription of Th2-specific genes by GATA3. J. Immunol. 186:6378-89.
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.
Pai SY, Truitt ML, Ho IC. GATA-3 deficiency abrogates the development and maintenance of T helper type 2 cells. Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):1993-8.
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.
Ram Raj Singh (2003). IL-4 and many roads to lupuslike autoimmunity. Clinical Immunology 108: 73-79.
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.
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.
Cunningham, M., Gilkeson, G., 2011. Estrogen receptors in immunity and autoimmunity. Clinical Reviews in Allergy and Immunology 40, 66-73.
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.