STAT6 and IL-4/IL-13 Dependent Gene Expression

IL-4和IL-13通过作用于多种细胞，在免疫介导的炎症中发挥重要作用。 人口数量。这些作用部分依赖于趋化因子基因表达的调节， 以及抑制对IFN γ的反应。趋化因子表达的变化 通过控制肿瘤和白细胞， 贩卖人口信号传导和转录因子STAT 6在许多（尽管不是全部）IL-10中起着必要的作用。 4/IL-13刺激的基因表达变化。其机制涉及基因表达的抑制， 尤其是，人们对它的了解还很少。在具体目标1中，我们将检查IL-4/IL-13介导的STAT 6 - 1。 依赖性抑制作用，并将测试抑制依赖于特定蛋白质的假设 通过STAT 6介导的相互作用。我们最近观察到IFNy诱导的 在STAT 6缺陷细胞中，趋化因子基因亚组的表达显著增强。具体目标2 我们将探索STAT 6这种明显的配体非依赖性抑制活性的机制基础， 评估STAT 6的结构特征、信号通路和基因启动子序列， 必需的. IFN γ和IL-4能够通过以下途径调节基因表达（阳性和阴性）： 分别独立于STAT 1或STAT 6和/或除了STAT 1或STAT 6之外还独立于STAT 6和/或除了STAT 1或STAT 6之外还独立于STAT 6和/或除了STAT 6和/或除了STAT 1或STAT 6之外还独立于STAT 6和/或除了STAT 6和/或除了STAT 1和STAT 6之外还独立于STAT 6和/或除了STAT 6和/或除了STAT 1和STAT 6之外还独立于STAT 6和/或除了STAT 6和/或STAT 6之外还独立于STAT 6和/或除了STAT 1和STAT 6之外还独立于STAT 6和/或除了STAT 6之外还独立于STAT 6和/或除了STAT 1和STAT 6之外还独立于STAT 6和/或除了STAT 1和STAT 6之外还独立于STAT 6和/或除了STAT 6之外还独立于STAT 1和STAT 6之外还独立于STAT 6和/或除了STAT 1和STAT 6之外还独立于STAT 6和/或STAT 6。使用 我们已经鉴定了一小部分趋化因子基因， IL-4可诱导从STAT 6 +/+和STAT 6-/-细胞获得的巨噬细胞中的表达， 小鼠在具体目标3中，我们将研究IL-4/IL-13介导的，STAT 6非依赖性的 通过分析IL-4 Ra受体结构、信号传导事件和启动子诱导MCP-2和MCP-5 负责特定基因行为的序列。同时，拟议研究的结果将导致 对不同细胞类型产生高度多样性反应的机制的理解 这些重要的免疫调节细胞因子。

IL-4 and IL-13 play important roles in immune-mediated inflammation through effects on a variety of cell populations. These actions depend in part on modulation of chemokine gene expression and include induction of new genes as well as inhibition of responses to IFNy. Changes in chemokine expression are now recognized to significantly impact the host-tumor relationship by controlling both tumor and lukocyte trafficking. The signaling and transcription factor STAT6 plays a requisite role in much (though not all) IL- 4/IL-13-stimulated change in gene expression. Mechanisms involved hi suppression of gene expression, particularly, remain poorly understood. In Specific Aim 1 we will examine IL-4/IL-13-mediated STAT6- dependent inhibitory action and will test the hypothesis that suppression depends upon specific proteinprotein interactions mediated through the STAT6 TAD. We have recently observed that IFNy-induced expression of a subset of chemokine genes is markedly enhanced STAT6 deficient cells. In Specific Aim 2 we will explore the mechanistic basis for this apparently ligand-independent inhibitory activity of STAT6 by evaluating the structural features of STAT6, the signaling pathways, and gene promoter sequences that are required. IFNy and IL-4 are capable of regulating gene expression (both positive and negative) through pathways that operate independently of and/or in addition to STAT1 or STAT6, respectively. Using Affymetrix oligonucleotide microarray analyses we have identified a small subset of chemokine genes whose expression can be induced comparably by IL-4 in macrophages obtained from both STAT6+/+ and STAT6-/- mice. In Specific Aim 3 we will examine the mechanisms for IL-4/IL-13-mediated, STAT6-independent induction of MCP-2 and MCP-5 by analysis of IL-4Ra receptor structure, signaling events, and promoter sequences responsible for specific gene behavior. In concert, the results of the proposed studies will lead to mechanistic understanding of the means through which distinct cell types develop highly diverse responses to these important immunoregulatory cytokines.