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

• 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
• 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

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（由申请人提供）：维生素及其代谢物对于调节免疫系统等许多生理过程至关重要，例如，维生素 D3 (VD3) 可以影响免疫细胞的功能，包括巨噬细胞、树突状细胞 (DC)、B 细胞。 25-羟基维生素 D3 (25(OH)VD3) 是 VD3 的主要循环形式，而 1,25(OH)2VD3 是最具生理意义的形式。有趣的是，据报道，患有自身免疫性疾病的患者中 25(OH)VD3 的血清水平降低，包括类风湿性关节炎 (RA)、系统性红斑狼疮 (SLE)、I 型糖尿病 (DM) 和多发性硬化症。事实上，多发性硬化症患者和患有实验性过敏性脑炎的小鼠（EAE，多发性硬化症动物模型）补充 VD3 可以减少他们的疾病，尽管这些研究结果支持了这一作用。 VD3 在自身免疫中的作用，其机制在很大程度上尚不清楚，因为它为补充 VD3 提供了科学依据，并可导致开发产生白细胞介素 17 (IL-17) 的自身免疫 T 的新疗法。辅助 17 (Th17) 细胞和叉头框 P3 (FOXP3) 阳性调节性 T 细胞（以下称为 FOXP3+ Treg）在自身免疫和炎症中发挥着重要作用。群体可能包含两个子集，一个是由胸腺发育而来的天然 Treg (FOXP3+ nTreg)，另一个是由外周常规 CD4+ T 细胞诱导的 (FOXP3+ iTreg)，以及 IL-17 数量和数量的改变。 FOXP3+ Treg 的功能与各种自身免疫性疾病的动物模型及其人类盟友有关。研究表明 Th17 细胞和 FOXP3+ iTreg 的分化。呐目前的申请提出了这样的假设：1,25(OH)2VD3 直接调节人 CD4+ T 细胞中的 FOXP3 和 IL-17 基因表达，从而促进 FOXP3+iTreg 的发育。 Th17 细胞分化和 IL-17 产生的相互抑制 该应用的目标是通过以下具体目标来解决这一假设： 目标 1) 研究 的影响。 1,25(OH)2VD3 对 FOXP3+ iTreg 和 Th17 细胞发育的影响以及人类 CD4+ T 细胞中此类作用的机制；目标 2) 研究 1,25(OH)2VD3 介导的 FOXP3 和 IL- 的分子机制17 通过识别和表征人类 FOXP3 和 IL-17 基因中维生素 D 受体的结合位点进行基因调控。通过 FOXP3+ Treg 和 Th17 细胞确定自身免疫与 VD3 之间的机制联系，并为在自身免疫中补充 VD3 以及使用 VD3 及其类似物开发新疗法提供科学依据。 公共健康相关性：众所周知，维生素可以调节 CD4+ T 细胞（一种白细胞）等免疫细胞。当前应用的目标是研究维生素 D 对两种不同的 CD4+ T 细胞亚群：辅助性 T 细胞 17 的影响。具有炎症特性的调节性 T 细胞和具有抗炎特性的调节性 T 细胞将增进我们对维生素 D 如何用作改善人类炎症的治疗剂的认识。