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Event: 1712

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Increase of Th2 cells producing IL-4

Short name

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Biological Context

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Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Cell term
T-helper 2 cell

Organ term

Organ term
immune system

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
Binding to ER-α leading to exacerbation of SLE	KeyEvent	Cataia Ives (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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Life Stages

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

Life stage	Evidence
All life stages

Sex Applicability

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

Term	Evidence
Mixed

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

In naive CD4+ T cells, T cell expansion shifts toward a Th2 phenotype that produces Th2 cytokines such as IL-4, IL-5, IL-10, and IL-13, thereby increasing antibody production from autoantibody-producing B cells. 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). Th2 cells produce IL-4, which stimulates B-cells to proliferate, to switch immunoglobulin classes, and to differentiate into plasma and memory cells. The receptor for IL-4 is IL-4Rα, which expresses in B cells. IL-4 also plays an important role in the development of certain immune disorders, particularly allergies and some autoimmune diseases and especially when there is Th2 polarization. Th2 cells from GATA3 and STAT6 knockout animals showed reduction in IL-4 production (Zhu J. 2004, Pai SY. 2004).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

The levels of IL-4 in the cell supernatants were determined by a sandwich enzyme-linked immunosorbent assay (ELISA), cytometric bead array (CBA) kits, or immunoblot analysis (Lee MH. 2003, Huimin Y. 2008, Lee J. 2010), and mRNA levels of IL-4 in the cells were assayed by reverse transcription–polymerase chain reaction (RT-PCR) (Lee MH. 2003, Lee J. 2010).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

Production of IL-4 from Th2 is common in humans, rodents, and other mammalian species.

References

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

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.
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.
Lee, MH, 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.
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.
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.