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  • Review Article
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Regulation of IL4 gene expression by T cells and therapeutic perspectives

Key Points

  • Interleukin-4 (IL-4) is a key cytokine that controls the differentiation of T helper (TH) cells to the TH2 effector cells that are responsible for cellular immunity and inflammation.

  • Expression of the gene encoding IL-4 by T cells is regulated in two steps — the early stages of T-cell differentiation and the later stage of acute gene expression by differentiated TH2 effector cells.

  • During the first stage, the transcription factor GATA3 (GATA-binding protein 3), which is expressed during TH2-cell differentiation, induces chromatin remodelling at various control regions of the IL4 gene, leading to de-condensation of the IL4 locus.

  • Acute expression of the IL4 gene by differentiated TH2 cells is regulated by many positive and negative inducible transcription factors, such as nuclear factor of activated T cells (NFAT) proteins, AP1, nuclear factor-κB, interferon regulatory factor 1 (IRF1) and other factors that bind the promoter and enhancer elements and coordinately achieve a fine degree of control over the transcriptional activity of the gene.

  • As acute expression of IL-4 by TH2 effector cells has a central role in the pathogenesis of allergic diseases, a better understanding of the regulatory mechanisms for IL4 gene expression might provide greater possibilities to develop therapeutic strategies. Recently, studies with vitamin E, aspirin and parthenolide have shown the potential of intervening at the level of transcription of the IL4 gene.

Abstract

Interleukin-4 (IL-4) is crucial for the differentiation of naive T helper (TH) cells into the TH2 effector cells that promote humoral (antibody) immunity and provide protection against intestinal helminths. IL-4 also has a central role in the pathogenesis of allergic inflammation. Many transcription factors are involved in the regulation of expression of the gene encoding IL-4. Initiation of transcription of the gene encoding IL-4 in naive TH cells is regulated by the TH2-specific transcription factor GATA3, whereas acute expression of the gene encoding IL-4 in TH2 cells is mediated by inducible, ubiquitous transcription factors after antigen encounter. This review focuses on acute activation of the gene encoding IL-4 in T cells and discusses therapeutic perspectives at the transcriptional level.

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Figure 1: Regulation of TH-cell development.
Figure 2: Immune pathways of allergic disease.
Figure 3: Overview of the regulatory regions around the IL4 locus.
Figure 4: Activation of IL4 transcription by NFAT and AP1 after T-cell activation.
Figure 5: Activation of IL4 transcription by NF-κB after T-cell activation.
Figure 6: Suppression of IL4 transcription by IRF1 and IRF2 after IFN-γ treatment.

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Acknowledgements

We thank S. Baumann and R. Arnold for critical reading of the manuscript.

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Correspondence to Min Li-Weber.

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DATABASES

LocusLink

CIITA

CP2

GATA3

HMG I(Y)

IFN-γ

IκBα

IKKα

IKKβ

IKKγ

IL-4

IL-4R

IL-5

IL-6

IL-10

IL-12

IL-12R

IL-13

IRF1

IRF2

IRF4

JAK1

JAK2

lymphotoxin

MAF

NFAT1

NFAT2

NFAT3

NFAT4

NFAT5

NF-κB2

NF-IL6

NF-IL6β

NFY

p65

PKCθ

c-REL

STAT1

STAT4

STAT6

T-bet

TNF

YY1

Glossary

ATOPIC DISORDERS

Asthma, rhinitis and hayfever are atopic disorders characterized by high serum levels of immunoglobulin E and skin sensitization to common environmental allergens.

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Li-Weber, M., Krammer, P. Regulation of IL4 gene expression by T cells and therapeutic perspectives. Nat Rev Immunol 3, 534–543 (2003). https://doi.org/10.1038/nri1128

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