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

STAT6 和 IL-4/IL-13 依赖性基因表达

• 批准号: 6942226
• 负责人: THOMAS A. HAMILTON
• 金额: $ 21.07万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-12 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6942226
• 关键词: biological signal transduction; cytokine receptors; gene induction /repression; genetic promoter element; interleukin 13; interleukin 4; laboratory mouse; protein protein interaction; transcription factor

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.

IL-4和IL-13通过作用于多种细胞在免疫介导性炎症中发挥重要作用 人口。这些作用在一定程度上依赖于趋化因子基因表达的调节，包括诱导 新基因以及对IFNy反应的抑制。趋化因子表达的变化现在是 被认为通过控制肿瘤和狼疮细胞显著影响宿主-肿瘤关系 贩卖人口。信号和转录因子STAT6在许多(尽管不是全部)IL-1中起着必要的作用。 4/IL-13刺激后基因表达的改变。机制涉及到抑制基因表达， 特别是，人们对此仍然知之甚少。在特定目标1中，我们将检测IL-4/IL-13介导的STAT6- 依赖的抑制作用，并将检验抑制依赖于特定蛋白质的假设 通过STAT6TAD介导的相互作用。我们最近观察到IFNY诱导的 趋化因子基因的一个子集的表达显著增强了STAT6缺陷细胞。《特定目标2》 我们将通过以下方式探索STAT6这种明显的配体非依赖性抑制活性的机制基础 评估STAT6的结构特征、信号通路和基因启动子序列 必填项。IFNY和IL-4能够通过以下途径调节基因表达(包括阳性和阴性) 分别独立于STAT1或STAT6和/或附加于STAT1或STAT6运行的通路。vbl.使用 Affymetrix寡核苷酸微阵列分析我们已经确定了趋化因子基因的一小部分 从STAT6+/+和STAT6-/-获得的巨噬细胞均可被IL-4类似地诱导表达 老鼠。在特定目标3中，我们将研究IL-4/IL-13介导的、STAT6非依赖的机制 通过分析IL-4ra受体结构、信号事件和启动子诱导MCP-2和MCP-5的表达 负责特定基因行为的序列。同时，拟议研究的结果将导致 对不同类型的细胞产生高度不同的反应的方式的机械性理解 这些重要的免疫调节细胞因子。