Interleukin-4 is a prototypic type I cytokine that is a central regulator of allergic inflammatory responses. It controls polarization of naive CD4 T cells to the TH2 phenotype and Ig class switching to IgE. The Cytokine Biology Unit has characterized the signaling mechanims utilized by the IL-4 receptor. It has been shown that activation of the latent transcription factor, Stat 6 controls both TH2 polarization and IgE class switching. In addition, IL-4-mediated Stat6 activation rescues activated naive CD4 T cells from apoptosis. Studies with mutant IL-4 receptor retroviruses have aided in the characterization of the molecular basis of receptor function. Similarly, the use of array analysis has identified a series of candidate genes that are important in the function of TH2 cells; detailed analysis of the roles of these genes and their protein products is now ongoing. In parallel with these studies are analyses of the control of TH2 induction and the regulation of IL-4 production. Utilizing mice in which the gene for the green fluorescence protein (GFP) has replaced the first exon of the IL-4 gene, it has been shown that the process of commitment to IL-4 production is a two- (or perhaps multi-) step process. In the first step, both IL-4 alleles are rapidly made accessible so that all cells subjected to short-term TH2 priming acquire the ability to produce IL-4, although at a low probability; so that most cytokine prositve cells express only a single IL-4 allele (monoallelism). Whether a cell will actually transcribe an IL-4 allele is probably determined by the set and quantity of key transcription factors. This initial differentiation event is followed by a less frequent event that renders one of the IL-4 alleles more likley to be transcribed and creates a epigenetic allelic preference that is most easily observed in cell clones. In these cases, a majority of the cells express only one or the other allelic product. The ratio of expressed alleles varies greatly among clones although it is highly stable within each clone. This type of monoallelic expression may be a very general mechanism that can be used to control the synthesis of """"""""dangerous"""""""" (but essential) molecules.
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