Regulation of IL-2 expression by the transcription factor Ets-1

转录因子 Ets-1 对 IL-2 表达的调节

• 批准号: 7573926
• 负责人: I-CHENG HO
• 金额: $ 8.88万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-20 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7573926
• 关键词: Affect; Autoimmune Diseases; Bacteria; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell physiology; Cells; DNA Binding; Defect; Development; Event; Goals; Hand; Helper-Inducer T-Lymphocyte; Immune; Immune response; In Vitro; Infectious Agent; Inflammatory Bowel Diseases; Interferons; Interleukin-10; Interleukin-2; Left; Light; Molecular; Multiple Sclerosis; Mus; Mutation; Outcome; Pathology; Peripheral; Phosphorylation; Phosphorylation Site; Play; Production; Protein Isoforms; Regulation; Role; T memory cell; T-Lymphocyte; Th1 Cells; Therapeutic Intervention; Time; Virus; c-ets1 transcription factor; cell growth; cell type; extracellular; in vivo; mutant; public health relevance; response

DESCRIPTION (provided by applicant): T helper cells differentiate into different subsets, which are responsible for controlling the outcome of an immune response. For example, Th1 cells direct the immune response against viruses and intracellular bacteria, while Th17 cells are required to eradicate certain extracellular bacteria. However, dysregulated T helper responses can cause immune pathology such as inflammatory bowel disease or multiple sclerosis. The transcription factor Ets-1 plays a major role in promoting IL-2 and IFN-? production and Th1 differentiation. At the same time, Ets-1 inhibits Th17 differentiation mainly through promoting IL-2. In addition to affecting T helper cell differentiation, IL-2 plays a pivotal role in immune regulation. While it is required for the induction of T cell memory, IL-2 also maintains regulatory T cells and therefore peripheral tolerance. The first aim of this proposal is directed at elucidating the molecular mechanisms by which Ets-1 regulates IL-2 production. Secondly, Ets-1 is expressed both in Th1 and Th17 cells, although it inhibits differentiation of the latter. It is unknown how Ets-1 activity is regulated in T cells. Activating and inactivating phosphorylation events that have been proposed in other cell types only play a very modest role in T cells. Therefore, other regulatory mechanisms must exist. Dr. Grenningloh has recently identified a mutant of Ets-1 that fails to promote IL-2 or IFN-? production. The second part of this proposal aims at identifying the defect of this mutant on a molecular level. This should shed light on the regulation of Ets-1 activity in T cells as opposed to other cell types. PUBLIC HEALTH RELEVANCE: T helper cells direct the immune response against infectious agents but can also cause autoimmune disease. The goal of this study is to understand the function of a transcription factor, Ets-1, that regulates T helper cell function and might therefore be a useful target for the development of new treatments.

描述（由申请人提供）：T辅助细胞分化成不同的亚群，负责控制免疫反应的结果。例如，Th1 细胞指导针对病毒和细胞内细菌的免疫反应，而 Th17 细胞则需要根除某些细胞外细菌。然而，辅助 T 细胞反应失调可能会导致免疫病理，例如炎症性肠病或多发性硬化症。转录因子Ets-1在促进IL-2和IFN-α的产生中起主要作用。生产和 Th1 分化。同时，Ets-1主要通过促进IL-2抑制Th17分化。除了影响 T 辅助细胞分化外，IL-2 在免疫调节中也发挥着关键作用。虽然 IL-2 是诱导 T 细胞记忆所必需的，但它还可以维持调节性 T 细胞，从而维持外周耐受性。该提案的第一个目的是阐明 Ets-1 调节 IL-2 产生的分子机制。其次，Ets-1 在 Th1 和 Th17 细胞中均表达，尽管它抑制后者的分化。目前尚不清楚 T 细胞中 Ets-1 活性如何受到调节。在其他细胞类型中提出的激活和失活磷酸化事件在 T 细胞中仅发挥非常有限的作用。因此，必须存在其他监管机制。 Grenningloh 博士最近发现了一种 Ets-1 突变体，该突变体无法促进 IL-2 或 IFN-α 的产生。生产。该提案的第二部分旨在从分子水平上识别该突变体的缺陷。这应该有助于阐明 T 细胞（而不是其他细胞类型）中 Ets-1 活性的调节。公共卫生相关性：辅助 T 细胞指导针对传染源的免疫反应，但也可能导致自身免疫性疾病。本研究的目的是了解转录因子 Ets-1 的功能，该因子调节 T 辅助细胞功能，因此可能成为开发新疗法的有用靶点。