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.
| Roman, Jessica; Rangasamy, Tirumalai; Guo, Jia et al. (2010) T-cell activation under hypoxic conditions enhances IFN-gamma secretion. Am J Respir Cell Mol Biol 42:123-8 |
| Keen, Judith C; Cianferoni, Antonella; Florio, Giovanni et al. (2006) Characterization of a novel PMA-inducible pathway of interleukin-13 gene expression in T cells. Immunology 117:29-37 |
| Guo, J; Casolaro, V; Seto, E et al. (2001) Yin-Yang 1 activates interleukin-4 gene expression in T cells. J Biol Chem 276:48871-8 |
