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: 7706357
• 负责人: Insoo Kang
• 金额: $ 20.69万
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7706357
• 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; 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E及其代谢产物对许多生理过程（包括调节免疫系统）至关重要。例如，维生素D3（VD 3）可以影响免疫细胞的功能，包括巨噬细胞、树突细胞（DC）、B和T细胞。25-羟基维生素D3（25（OH）VD 3）是VD 3的主要循环形式，而1，25（OH）2 VD 3是VD 3的最具生理活性的形式。令人感兴趣的是，在患有自身免疫性疾病（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（MS））的患者中已经报道了25（OH）VD 3的血清水平降低。事实上，MS患者和实验性过敏性脑炎（EAE，MS动物模型）小鼠中的VD 3补充剂减轻了他们的疾病。虽然这些发现支持VD 3在自身免疫中的作用，但其机制在很大程度上尚不清楚。解决这个问题至关重要，因为它为补充VD 3提供了科学依据，并可能导致开发新的自身免疫治疗方法。产生白细胞介素-17（IL-17）的辅助性T细胞17（Th 17）和叉头框P3（FOXP 3）阳性调节性T细胞（以下称为FOXP 3 + Treg）在自身免疫和炎症中起主要作用。Treg群体可能包含两个亚群，一个称为从胸腺发育的天然存在的Treg（FOXP 3 + nTreg），另一个称为从外周中的常规CD 4 + T细胞诱导的Treg（FOXP 3 + iTreg）。IL-17的过度产生以及FOXP 3 + Treg的数量和功能的改变与各种自身免疫性疾病的动物模型及其人类对应物有关。研究表明，Th 17细胞和FOXP 3 + iTreg从幼稚CD 4 + T细胞的分化具有相互关系。本申请解决了以下假设：1，25（OH）2 VD 3直接调节人CD 4 + T细胞中的FOXP 3和IL-17基因表达，导致FOXP 3 +iTreg的发育增强，同时相互抑制Th 17细胞分化和IL-17产生。本申请的目的是通过以下具体目的来解决该假设：目的1）研究1，25（OH）2 VD 3对发育中的FOXP 3 + iTreg和Th 17细胞的作用以及在人CD 4 + T细胞中这种作用的潜在机制;和目的2）研究1，通过鉴定和表征人FOXP 3和IL-17基因中维生素D受体的结合位点，25（OH）2 VD 3介导的FOXP 3和IL-17基因调节。拟议研究的结果将通过FOXP 3 + Treg和Th 17细胞确定自身免疫与VD 3之间的机制联系，并为在自身免疫中补充VD 3和开发VD 3及其类似物的新治疗方法提供科学依据。 公共卫生相关性：众所周知，维生素可以调节免疫细胞，如CD 4 + T细胞，一种白色血细胞。本申请的目的是研究维生素D对两种不同的CD 4 + T细胞亚群的影响：具有炎症特性的辅助性T细胞17和具有抗炎特性的调节性T细胞。这些研究的结果将推进我们对维生素D如何用作治疗剂以改善人类炎症的认识。