INHIBITION OF IL4 EXPRESSION IN CELLS RELEVANT TO ASTHMA

白细胞介素（IL-4）是一种由活化的T细胞、嗜碱性细胞和肥大细胞产生的细胞因子，在细胞和体液免疫反应中起重要作用。由于IL-4能够促进炎症细胞向气道募集、B细胞中IgE同型转换以及CD4+ T细胞向Th2表型分化，因此IL-4表达失调与哮喘的发展密切相关。越来越多的证据表明，这种失调涉及IL-4基因转录调节的主要改变。对抑制IL-4转录的因素所知相对较少。例如，糖皮质激素（GC）是治疗哮喘最有效的单一药物，其抑制IL-4产生的机制尚不清楚。我们发现GC直接抑制由IL-4启动子驱动的转录，并且通过电泳迁移量转移试验（EMSA），我们发现了一个激活诱导的GC敏感核蛋白复合物（复合物I），该复合物与一个关键的IL-4启动子元件结合。此外，我们发现多功能转录因子阴阳（YY1）可以与IL-4启动子中的多个元件相互作用，并且YY1强烈抑制IL-4的转激活，并在不同的哮喘受试者（包括具有类固醇抗性表型的哮喘患者）中研究了这些机制。其次，我们将验证YY1以序列特异性方式抑制IL-4启动子的假设。这些研究有助于加深我们对IL-4基因表达的认识。

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.