Studying the effects of vitamin D on FOXP3 and IL-17 expression in human CD4+ T c

研究维生素 D 对人 CD4 T c 中 FOXP3 和 IL-17 表达的影响

基本信息

批准号：
7938575
负责人：
Insoo Kang
金额：
$ 20.48万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7938575
关键词：
Address Affect Animal Model Anti-Inflammatory Agents Anti-inflammatory Autoimmune Diseases Autoimmunity Binding Binding Sites Boxing CD4 Positive T Lymphocytes Calcifediol Cell Differentiation process Cell Nucleus Cells Characteristics Cholecalciferol DNA Dendritic Cells Development Diabetes Mellitus Diet Disease Experimental Autoimmune Encephalomyelitis Figs - dietary Gene Expression Gene Expression Regulation Generations Genes Goals Human IL2RA gene Immune Immune response Immune system Inflammation Inflammatory Insulin-Dependent Diabetes Mellitus Interleukin-17 Interleukin-2 Interleukin-4 Interleukin-6 Kidney Knowledge Lead Leukocytes Link Liver Mediating Memory Molecular Multiple Sclerosis Mus Patients Physiological Processes Play Population Production Property Regulation Regulatory T-Lymphocyte Reporting Rheumatoid Arthritis Role Serum Skin Supplementation Systemic Lupus Erythematosus T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Therapeutic Agents Thymus Gland Up-Regulation Vitamin A Vitamin D Vitamin D3 Receptor Vitamins analog base cytokine immune function improved interest interleukin-23 macrophage memory CD4 T lymphocyte public health relevance receptor response

项目摘要

DESCRIPTION (provided by applicant): Vitamins and their metabolites are essential for a number of physiological processes including regulating the immune systems. For instance, vitamin D3 (VD3) can affect the functions of immune cells including macrophages, dendritic cells (DC), B and T cells. 25-hydroxyvitamin D3 (25(OH)VD3) is the main circulating form of VD3 whereas 1,25(OH)2VD3 is the most physiologically active form of VD3. Of interest, decreased serum levels of 25(OH)VD3 have been reported in patients with autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type I diabetes mellitus (DM) and multiple sclerosis (MS). In fact, VD3 supplementation in patients with MS and mice with experimental allergic encephalitis (EAE, animal model of MS) reduced their disease. Although these findings support a role for VD3 in autoimmunity, its mechanism(s) is largely unknown. Addressing this issue is critical since it provides a scientific rationale for supplementing VD3 as well as can lead to developing new treatments in autoimmunity. Interleukin-17 (IL-17)-producing T helper 17 (Th17) cells and forkhead box P3 (FOXP3)-positive regulatory T cells (hereafter called FOXP3+ Treg) play major roles in autoimmunity and inflammation. The Treg population likely contains two subsets, one called naturally occurring Treg developed from the thymus (FOXP3+ nTreg) and the other one induced from conventional CD4+ T cells in the periphery (FOXP3+ iTreg). Overproduction of IL-17 as well as alterations in the numbers and function of FOXP3+ Treg have been linked to animal models of various autoimmune diseases and their human counterparts. Studies suggest that the differentiation of Th17 cells and FOXP3+ iTreg from na¿ve CD4+ T cells have a reciprocal relationship. The current application address the hypothesis that 1,25(OH)2VD3 directly regulates the FOXP3 and IL-17 gene expression in human CD4+ T cells, leading to the enhanced development of FOXP3+iTreg with a reciprocal suppression of Th17 cell differentiation and IL-17 production. The goal of the application is addressing the hypothesis with the following specific aims: Aim 1) Investigate the effects of 1,25(OH)2VD3 on developing FOXP3+ iTreg and Th17 cells as well as the mechanisms underlying such effects in human CD4+ T cells; and Aim 2) Investigate the molecular mechanism underlying 1,25(OH)2VD3-mediated FOXP3 and IL-17 gene regulation through identifying and characterizing the binding site(s) of the vitamin D receptor in the human FOXP3 and IL-17 genes. The results of the proposed studies will identify a mechanistic link between autoimmunity and VD3 via FOXP3+ Treg and Th17 cells and provide a scientific rationale for supplementing VD3 in autoimmunity and developing new treatments with VD3 and its analogues. Public Health Relevance: Vitamins are known to modulate immune cells like CD4+ T cells, a type of white blood cells. The goal of the current application is to investigate the effects of vitamin D on two different CD4+ T cell subsets: T-helper 17 cells with inflammatory property and regulatory T cells with anti-inflammatory property. The results of the studies will advance our knowledge on how vitamin D can be used as a therapeutic agent to improve inflammation in humans.

描述（由适用提供）：维生素及其代谢物对于许多生理过程至关重要，包括调节免疫系统。例如，维生素D3（VD3）可以影响包括巨噬细胞，树突状细胞（DC），B和T细胞在内的免疫细胞的功能。 25-羟基维生素D3（25（OH）VD3）是VD3的主要循环形式，而1,25（OH）2VD3是VD3的最活跃形式。感兴趣的是，在包括类风湿关节炎（RA），全身性红斑红细胞（SLE），I型糖尿病（DM）和多发性硬化症（MS）在内的自身免疫性关节炎（RA），全身性狼疮性红细胞（SLE），包括类风湿关节炎（RA），全身性红斑狼疮（SLE）和多发性硬化症（MS）的患者中，血清水平提高了25（OH）VD3。实际上，患有实验性过敏性脑炎的MS和小鼠患者的VD3补充（MS的动物模型）降低了疾病。尽管这些发现支持VD3在自身免疫中的作用，但其机制在很大程度上是未知的。解决此问题至关重要，因为它为补充VD3提供了科学原理，并可能导致自动免疫的新治疗方法。白介素17（IL-17） - 产生T辅助辅助器17（Th17）细胞和叉子盒P3（Foxp3） - 阳性调节T细胞（以下称为Foxp3+ Treg）在自身免疫和炎症中起主要作用。 Treg种群可能包含两个子集，一个子集，一种称为自然发生的Treg，是由胸腺（Foxp3+ Ntreg）发育而来的，另一个称为外周（FOXP3+ ITREG）中的常规CD4+ T细胞引起的另一个子集。 IL-17的过量生产以及Foxp3+ Treg的数量和功能的改变与各种自身免疫性疾病及其人类的动物模型有关。研究表明，Th17细胞和FOXP3+ ITREG与Na�VECD4+ T细胞的分化具有相互关系。当前的应用程序解决了以下假设：1,25（OH）2VD3直接调节人CD4+ T细胞中FOXP3和IL-17基因的表达，从而通过对Th17细胞分化和IL-17产生的相互抑制，从而增强了Foxp3+ ItReg的发展。该应用的目的是以以下具体目的解决该假设：目标1）研究1,25（OH）2VD3对开发Foxp3+ ITREG和TH17细胞的影响，以及在人CD4+ T细胞中产生这种影响的机制；目标2）通过鉴定和表征人Foxp3和IL-17基因中维生素D受体的结合位点（S）来研究1,25（OH）2VD3介导的FOXP3和IL-17基因调节的分子机制。拟议的研究的结果将通过Foxp3+ Treg和Th17细胞确定自身免疫和VD3之间的机械联系，并为补充自身免疫性中的VD3提供了科学理由，并使用VD3及其类似物开发新的治疗方法。公共卫生相关性：已知维生素可以调节一种白细胞CD4+ T细胞等免疫细胞。当前应用的目的是研究维生素D对两个不同CD4+ T细胞子群的影响：具有炎症特性的T辅助17细胞和具有抗炎特性的调节性T细胞。研究结果将提高我们如何将维生素D用作治疗剂来改善人类炎症的知识。