Interleukin 4

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Abstract

Summary Interleukin-4 is a prototypic type I cytokine that is the central regulator of allergic inflammatory responses. It controls the polarization of naive CD4 T cells to the TH2 phenotype and Ig class switching to IgE. The Cytokine Biology Unit has characterized the signaling mechanisms utilized by the IL-4 receptor. It has shown that activation of the latent transcription factor, Stat 6, controls both TH2 polarization and IgE class switching. In addition, IL-4-mediated Stat6 signaling rescues activated naive CD4 T cells from apoptosis. During the past year, scientists in the Unit have shown that activation of the ERK signaling pathway prevents transcription of GATA3 and desensitizes the IL-2 receptor. Both GATA3 and IL-2 are essential for early transcription of IL-4, which in turn controls TH2 differentiation. Since high concentrations of antigen strongly stimulate ERK phosphorylation, they prevent TH2 differentiation while low concentrations of antigen, which activate ERK only weakly, are permissive for early IL-4 production and TH2 differentiation. Utilizing conditional GATA3 knockout mice,it has been shown that GATA3 is essential for priming for IL-4-production but that cells that have already differentiated into Th2 cells can sustain their IL-4 producing capacity even when GATA3 is eliminated although both IL-5 and IL-13 production are strictly dependent on GATA3. It has been further demonstrated that GATA3 is a potent growth regulator of TH2 cells and that GATA3 and Gfi-1 act together to induce this striking stimulation of TH2 cell growth. Laboratory scientists have also demonstrated that the transcription of the two alleles at the Il4 locus is governed stochastically and that the likelihood of transcription is associated with the degree of chromatin accessibility of the two alleles. Furthermore, although there are shared requirements for the transcription of IL-4 and IL-13, in individual cells and individual clones, the expression of these cytokines is independently determined. LI scientists have also developed new insights into the production of IL-4 by basophils. They have shown that these cells are massively recruited into the tissues, spleen and blood in helminth infection and that this recruitment is T cell dependent. IL-3 appears to play a major role in basophil recruitment. Efforts are now underway to use genome-wide RNAi to screen for genes involved in IL-4 signaling and to use the techniques of recombineering to prepare mice in which various fluorescent "colors" are surrogates for in vivo gene expression. Initial efforts are to prepare a "red" reporter for IL-13.