INHIBITION OF IL4 EXPRESSION IN CELLS RELEVANT TO ASTHMA

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Interleukin (IL-4), a cytokine produced by activated T cells, basophils, and mast cells, plays an important role in cellular and humoral immune reactions. By virtue of its ability to promote inflammatory cell recruitment to the airway, IgE isotype switching in B cells, and the differentiation of CD4+ T cells toward the Th2 phenotype, dysregulated IL-4 expression is strongly linked to the development of asthma. Increasing evidence suggests that this dysregulation involves primary alterations in the transcriptional regulation of the IL-4 gene. Relatively little is known about the factors that repress IL-4 transcription. For example, the mechanism by which glucocorticoids (GC), the single most effective agents in the treatment of asthma, inhibit IL-4 production are not known. We discovered that GC directly repress transcription driven by the IL-4 promoter, and by electrophoretic mobility shift assays (EMSA), we identified an activation- induced, GC-sensitive nuclear protein complex (complex I) that bound to a critical IL-4 promoter element. Additionally, we found that the multifunctional transcription factor Yin-Yang (YY1) can interact with multiple elements in the IL-4 promoter, and that YY1 strongly inhibits IL-4 transactivation, and study these mechanisms in different subjects with asthma (including those with a steroid-resistant phenotype). Second, we will test the hypothesis that YY1 inhibits the IL-4 promoter in a sequence- specific manner. These studies should enhance our understanding of IL-4 gene expression.