Regulation of Ets-1 activity in Th cells

描述（由申请人提供）：为了对入侵的病原体产生有效的免疫反应，CD4+辅助性T （Th）细胞必须产生高水平的炎症细胞因子，包括IFN-？和TNF-a，但同时抑制抗炎细胞因子的表达，如IL-10。然而，失调的Th反应也会导致器官特异性自身免疫性疾病，如自身免疫性糖尿病、多发性硬化症和克罗恩病。促进IL-10的产生，抑制IFN-？和TNF-a已被证明对这类自身免疫性疾病有治疗作用。因此，通过Th细胞控制细胞因子的产生已成为感染性和自身免疫性疾病的一种新治疗方法，也是我们研究的长期目标。我们最近发现转录因子Ets-1相互调节Th细胞中炎症和抗炎细胞因子的产生，并且对于IFN-？和tnf -a介导的炎症反应。此外，在活化的Th细胞中，Ets-1发生磷酸化，并在细胞核和细胞质之间穿梭，表明Ets-1的功能在多个水平上受到调控。因此，Ets-1似乎是操纵免疫反应的理想靶点，具有很大的治疗潜力。在本次拨款申请中，我们计划进一步研究Ets-1的作用机制。我们对了解Ets-1的磷酸化和核/细胞质易位的调控和功能意义特别感兴趣。从拟议的实验中获得的知识将使我们能够开发出影响Ets-1功能的可行方法，并最终导致感染性和自身免疫性疾病的新治疗方法。

DESCRIPTION (provided by applicant): To mount effective immune responses against invading pathogens, CD4+ helper T (Th) cells have to produce high levels of inflammatory cytokines, including IFN-? and TNF-a, but simultaneously suppress the expression of anti-inflammatory cytokines, such as IL-10. However, dysregulated Th responses can also lead to organ-specific autoimmune diseases, such as autoimmune diabetes, multiple sclerosis, and Crohn's disease. Enhancing the production of IL-10 and suppressing the expression of IFN-? and TNF-a by Th cells have been shown to be therapeutic for such autoimmune diseases. Thus, manipulating the cytokine production by Th cells has emerged as a novel treatment for both infectious and autoimmune diseases and has been a long-term objective of our research. We recently discovered that the transcription factor Ets-1 reciprocally regulated the production of inflammatory and anti-inflammatory cytokines in Th cells, and was essential for mounting IFN-? and TNF-a-mediated Th inflammatory responses. In addition, Ets-1 underwent phosphorylation and was shuttled between the nucleus and cytoplasm in activated Th cells, indicating the function of Ets-1 is regulated at multiple levels. Therefore, Ets-1 appears to be an ideal target for manipulating Th immune responses and bears great therapeutic potential. In this grant proposal, we plan to further investigate the mechanism of action of Ets-1. We are particularly interested in understanding the regulation and functional significance of phosphorylation and nuclear/cytoplasm translocation of Ets-1. The knowledge gained from the proposed experiments will allow us to develop feasible approaches to influence the function of Ets-1 and eventually lead to novel treatments of infectious and autoimmune diseases.