REGULATION OF IL4 IN CELLS INVOLVED IN ALLERGIC DISEASE

过敏性疾病影响了30%的美国人口。细胞因子 白介素4通过以下途径在过敏反应中发挥核心作用 诱导LGE合成并通过刺激LGE合成的几个方面 炎症反应。过敏性疾病患者IL-4合成增加 IL-4在小鼠体内的过度表达和受试者导致发育 “类过敏性”炎症性疾病。IL-4的产生是 最初被描述为T辅助(Th)淋巴细胞。的确， 细胞因子谱分析用于定义三种功能 Th细胞亚群：THI，产生IL-2和干扰素v； Th2，产生IL-4和IL-5；Th0，具有混合表型。 然而，最近的研究表明，细胞不是 Th2/Th0可产生IL-4。例如，人的外周血液 嗜碱性细胞在体内释放大量的IL-4和其他细胞因子 膜结合型LGE对交联的响应。几项研究 提示产生IL-4的Th细胞和嗜碱性粒细胞的重要作用 在过敏性炎症的发病机制中。勾勒出 因此，IL-4基因激活的分子基础是中枢的 对我们了解过敏性疾病的重要性。 细胞因子相互排斥的机制(S) 在Th细胞亚群中的表达还不完全清楚。此外，没有 到目前为止，已经进行了一些研究来分析转录 嗜碱性粒细胞中ll4基因的激活。校长 调查人员详细研究了两个具有相反影响的因素 IL-2和IL-4基因的转录激活：核 因子(NF)Kb和CP2。这个项目的重点是两个具体的 目的：1)了解ILA基因调控的机制。 这些因子及其在人类差异基因表达中的作用 Th1和Th2克隆；2)研究IL-4的作用机制 人类嗜碱性粒细胞的基因调控，以确定可能的 转录激活剂介导LGE依赖的ILA表达 这些细胞。人提取蛋白的DNA结合分析 豚草抗原(Amb A I)特异性Th1和Th2的克隆和新鲜 嗜碱性粒细胞的分离纯化及IL-4启动子驱动分析 报告基因在人T细胞白血病Jurkat中的表达 用来实现这些目标的。定义转录因子 在Th细胞中调节人ILA基因的表达，并 从长远来看，嗜碱性细胞可能会导致新的治疗方法。 用于治疗过敏性疾病。

Allergic diseases affect 30% of the U.S. population. The cytokine interleukin (lL)-4 plays a central role in allergic responses by inducing lgE synthesis and by stimulating several aspects of the inflammatory response. Synthesis of lL-4 is increased in allergic subjects and overexpression of lL-4 in mice leads to the development of "allergic like" inflammatory disease. Production of IL-4 was originally described from T helper (Th) lymphocytes. Indeed, analysis of cytokine profiles was used to define three functional subpopulations of Th cells: ThI, producing lL-2 and interferon v; Th2, producing IL-4 and lL-5; and Th0, having a mixed phenotype. More recently, however, it has been shown that cells other than Th2/Th0 can produce IL-4. For example, human peripheral blood basophils release substantial amounts of lL-4 and other cytokines in response to Crosslinking of membrane-bound lgE. Several studies suggest an important role of lL-4 producing Th cells and basophils in the pathogenesis of allergic inflammation. Delineating the molecular basis of lL-4 gene activation is, therefore, of central importance to our understanding of allergic diseases. The mechanism(s) responsible for mutually exclusive cytokine expression in Th cell subsets are not fully understood. Moreover, no studies have been conducted so far to analyze the transcriptional activation of the lL4 gene in human basophils. The principal investigator has studied in detail two factors having opposite effects on transcriptional activation of the lL-2 and IL-4 genes: nuclear factor (NF)KB and CP2. This project is focused on two specific aims: 1) to understand the mechanisms of ILA gene regulation by these factors and their role in differential gene expression in human Th1 and Th2 clones, and 2) to investigate the mechanisms of lL-4 gene regulation in human basophils, to identify possible transcriptional activators mediating lgE-dependent ILA expression in these cells. DNA-binding assays with proteins extracted from human ragweed antigen (Amb a I)-specific Th1 and Th2 clones and freshly isolated, purified basophils and the analysis of IL4 promoter-driven reporter gene expression in the human T cell leukemia Jurkat will be used to accomplish these aims. Defining the transcriptional factors that regulate the expression of the human ILA gene in Th cells and basophils may, in the long term, lead to novel therapeutic approaches for the treatment of allergic disorders.