API

Event: 1712

Key Event Title

?

Increase of Th2 cells producing IL-4

Short name

?

Increase of Th2 cells producing IL-4

Biological Context

?

Level of Biological Organization
Cellular

Cell term

?

Cell term
T-helper 2 cell


Organ term

?

Organ term
immune system


Key Event Components

?

Process Object Action

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

Stressors

?


Taxonomic Applicability

?


Life Stages

?

Life stage Evidence
All life stages

Sex Applicability

?

Term Evidence
Mixed

Key Event Description

?


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

?


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

?


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


Evidence for Perturbation by Stressor



17beta-Estradiol

In vitro, the addition of E2 significantly increased IL-4 secretion from ERα-replete CD4+T cells, while this effect was abrogated in ERα-deficient CD4+T cells. (Lambert KC. 2005).


Bisphenol A

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 J. 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 Y. 2008).


References

?


  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.