Role of Histone Deacetylases 6 and 11 in regulation of IL-10 and immune responses

描述(申请人提供)：近年来，在机械理解促炎和抗炎细胞因子在调节针对抗原的免疫反应中的作用方面取得了重大进展，包括那些由肿瘤表达的抗原。然而，我们仍然对促炎/抗炎基因在其自然环境--染色质底物中的调节知之甚少。已经确定了几种机制，可以影响染色质的灵活性，并允许基因表达的动态变化。其中，组蛋白尾部乙酰化和脱乙酰化引起的染色质修饰受到了广泛关注。我们以前报道了组蛋白脱乙酰酶11(HDAC11)对IL-10表达的影响，最近我们发现HDAC6对IL-10产生的影响。这两种脱乙酰酶具有相反的调节作用，有趣的是，它们通过特定的结构域相互作用。在这项提案中，我们计划充分了解HDAC6和HDAC11/HDAC6蛋白复合体对抗原提呈细胞APC产生IL-10和其他细胞因子的作用，以及这种调控与APC介导的免疫反应的后果和相关性。我们还将研究HDAC11/HDAC6相互作用的作用、细胞定位和调控机制，以及取消这种蛋白质复合体的后果。这个项目将产生关于hDAC介导的IL-10和其他细胞因子的表观遗传控制的重要知识。这些信息将有助于更好地理解HDAC抑制剂对APC介导的免疫反应的控制机制。 与公共卫生相关：针对抗原的免疫反应的启动、大小和持续时间是严格调控的过程，涉及免疫细胞中促炎和抗炎途径的动态、精心安排的平衡。这种微妙的平衡对于允许对外来抗原进行有效的免疫反应，同时防止针对自身抗原的自身免疫攻击至关重要。最近，人们致力于从机制上理解促炎/抗炎基因在其自然环境--染色质底物中的调节。这一知识将有助于以更有针对性的方式开发新药和疗法，防止“其他”免疫途径的不受欢迎的激活/阻塞。在这个项目中，我们将研究组蛋白脱乙酰酶(HDACs)对抗炎细胞因子IL-10调控的影响，以及该基因的表观遗传调控如何影响抗原提呈细胞(APC)介导的免疫反应。

DESCRIPTION (provided by applicant): In recent years, significant advances have been made in mechanistically understanding the role of pro- and anti-inflammatory cytokines in the regulation of immune responses against antigens, including those expressed by tumors. However, we still know very little about the regulation of pro-/anti-inflammatory genes in its natural setting, the chromatin substrate. Several mechanisms have been identified that can influence chromatin flexibility and allow dynamic changes in gene expression. Among these, chromatin modifications induced by acetylation and deacetylation of histone tails have gained wide attention. We reported previously the role of the histone deacetylase 11 (HDAC11) on the expression of IL-10, and recently we discovered the effect of HDAC6 on IL-10 production. These two deacetylases have opposite regulatory effects, and interestingly, interact through specific domains. In this proposal we plan to fully understand the role of HDAC6 and the protein complex HDAC11/HDAC6 on the production of IL-10 and other cytokines in antigen presenting cells APCs, and the consequences and relevance of this regulation to the immune response mediated by APCs. We will also study the role, cellular localization and regulatory mechanisms ruled by the interaction of HDAC11/HDAC6, and the consequences of the abrogation of this protein complex. This project will generate important knowledge about the epigenetic control of IL-10 and other cytokines mediated by HDACs. This information will help contribute to a better understanding of the mechanistic action of HDAC inhibitors over the control of immune responses mediated by APCs. PUBLIC HEALTH RELEVANCE: The initiation, magnitude, and duration of an immune response against antigens are tightly regulated processes involving a dynamic, orchestrated balance of pro- and anti-inflammatory pathways in immune cells. Such a delicate balance is critical for allowing efficient immune response against foreign antigens while preventing autoimmune attack against self-antigens. Recently, significant effort has been devoted to mechanistically understanding regulation of pro-/anti-inflammatory genes in its natural setting, the chromatin substrate. This knowledge will help contribute to the development of new drugs and therapies in a more tailored fashion, preventing the undesired activation/blockage of "other" immune pathways. In this project we will study the influence of histone deacetylases (HDACs) on the control of the anti-inflammatory cytokine IL- 10, and how epigenetic regulation of this gene influences the immune response mediated by Antigen Presenting Cells (APCs).