Aging Vitamin E, and Immune Function in Aged

维生素E的老化与老年人的免疫功能

• 批准号: 7274800
• 负责人: SIMIN Nikbin MEYDANI
• 金额: $ 26.55万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7274800
• 关键词: Abbreviations; Age; Aging; Antibodies; Antigen-Presenting Cells; Biological Assay; Cell Cycle; Cell physiology; Cells; Ceramide Signaling Pathway; Ceramides; Cholesterol; Chromosome Pairing; Color; Communicable Diseases; Complex; Confocal Microscopy; Cytoskeletal Modeling; Data; Defect; Dietary Intervention; Dinoprostone; Disease; Elderly; Enzymes; Event; Figs - dietary; Genetic Transcription; Goals; High Pressure Liquid Chromatography; Human; I Kappa B-Alpha; Immune; Immunologic Suppressor Factors; Incidence; Inflammatory Response; Interleukin-2; Intervention; Label; Lead; Lipids; Mediating; Membrane; Membrane Lipids; Membrane Microdomains; Metabolic; Methionine; Microscopy; Modification; Morbidity - disease rate; Mus; NF-kappa B; Nuclear; Pathway interactions; Phosphorylation; Phosphotransferases; Production; Progress Reports; Prostaglandin Production; Prostaglandin-Endoperoxide Synthase; Proteins; Sampling; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Sphingolipids; Staining method; Stains; Structure; Supplementation; Synapses; T-Cell Receptor; T-Lymphocyte; TNF receptor-associated factor 6; TRAF6 gene; Techniques; Testing; Transcription Factor AP-1; Up-Regulation; Vitamin E; Western Blotting; age related; aged; base; cyclooxygenase 1; cyclooxygenase 2; design; immune function; improved; in vivo; inhibitor/antagonist; macrophage; mortality; palmitoylation; protein kinase C zeta; research study; synaptogenesis; tandem mass spectrometry; transcription factor; tumor

DESCRIPTION (provided by applicant): Aging is associated with a decline in T cell mediated functions, which contributes to a higher incidence of, and morbidity and mortality from, infectious diseases and tumors. The age-related defect in T cells has been shown to be due to intrinsic declines in T cell function, as well as increased production of prostaglandin (PG)E2, a T cell suppressive factor, by macrophages (Mphi). We demonstrated that the increased PGE2 production was due to ceramide mediated upregulation of cyclooxygenase 2 (COX-2) transcription, a key regulatory enzyme in PGE2 synthesis. The signaling mechanism through which ceramide upregulates COX 2 expression, however, is not known and needs to be investigated. We further showed that vitamin E (E) supplementation improves T cell mediated function by two distinct mechanisms: a) by decreasing PGE2 production, thus reducing macrophage Mphi mediated suppression, and b) by directly enhancing T cell function, independent of its effect on Mphi PGE2 production. E exerts its effect by improving the ability of naive T cells from old mice to produce IL-2 and progress through cell division cycles. The mechanism of E-induced enhancement of naive T cell function is not known and needs to be determined. Thus, the specific aims of this proposal are: 1) To determine the signaling pathway involved in ceramide-induced upregulation of COX-2 expression in old Mphi. To accomplish this goal, we will test the hypothesis that ceramide upregulates COX-2 expression in old macrophages through enhancing PKC-zeta activity, leading to increased IkappaB phosphorylation, and thus degradation. This in turn will increase NFkappaB activation and COX-2 expression. 2) To determine the mechanism of E-induced increase in the function of old naive T cells. To accomplish this goal, we will test the hypothesis that E enhances naive T cell function in old mice by increasing their ability to form an effective immune synapse at the site of T cell receptor (TCR) and antigen contact. This, in turn, will lead to improved TCR-associated signal transduction, and subsequent, IL-2 production in old mice. We propose that E induces its effect by changing the redistribution of key TCR associated signaling molecules in membrane lipid domains, known as lipid rafts, by one or both of the following mechanisms: a) increasing palmitoylation of key signaling molecules associated with TCR-mediated activation, and b) changing the structure of the lipid component of lipid rafts. These experiments will elucidate the mechanism of the age-related dysregulation of macrophages and T cells, as well as their normalization by E. This, in turn, will help in designing practical nutritional interventions to reverse and/or delay the age-associated dysregulation of immune and inflammatory responses as well as diseases associated with it.

描述（由申请人提供）：衰老与T细胞介导的功能下降有关，这导致感染性疾病和肿瘤的发病率、发病率和死亡率较高。T细胞中与年龄相关的缺陷已被证明是由于T细胞功能的内在下降，以及巨噬细胞（Mphi）产生的T细胞抑制因子前列腺素（PG）E2的增加。我们证明，增加PGE 2的生产是由于神经酰胺介导的上调环氧合酶2（考克斯-2）的转录，在PGE 2合成的关键调控酶。然而，神经酰胺上调考克斯2表达的信号机制尚不清楚，需要进一步研究。我们进一步表明，维生素E（E）补充通过两种不同的机制改善T细胞介导的功能：a）通过减少PGE 2产生，从而减少巨噬细胞Mphi介导的抑制，和B）通过直接增强T细胞功能，而不依赖于其对Mphi PGE 2产生的影响。E通过提高来自老年小鼠的幼稚T细胞产生IL-2的能力并通过细胞分裂周期进行发挥其作用。E诱导的初始T细胞功能增强的机制尚不清楚，需要确定。因此，这项建议的具体目标是： 1)确定神经酰胺诱导老年Mphi中考克斯-2表达上调的信号通路。为了实现这一目标，我们将检验神经酰胺通过增强PKC-zeta活性上调老年巨噬细胞中考克斯-2表达，导致IkappaB磷酸化增加，从而降解的假设。这反过来将增加NF κ B活化和考克斯-2表达。 2)确定E诱导老年初始T细胞功能增加的机制。为了实现这一目标，我们将测试的假设，E增强幼稚T细胞功能，在老年小鼠，通过增加他们的能力，形成一个有效的免疫突触的T细胞受体（TCR）和抗原接触的网站。反过来，这将导致老年小鼠中TCR相关信号转导的改善，以及随后的IL-2产生。我们提出，E通过改变膜脂质结构域（称为脂筏）中关键TCR相关信号分子的再分布来诱导其效应，其机制为以下一种或两种：a）增加与TCR介导的活化相关的关键信号分子的棕榈酰化，和B）改变脂筏的脂质组分的结构。 这些实验将阐明与年龄相关的巨噬细胞和T细胞失调的机制，以及它们被E。反过来，这将有助于设计实用的营养干预措施，以逆转和/或延迟与年龄相关的免疫和炎症反应失调以及与之相关的疾病。

项目成果

Age-dependent changes in the sphingolipid composition of mouse CD4+ T cell membranes and immune synapses implicate glucosylceramides in age-related T cell dysfunction.

• DOI: 10.1371/journal.pone.0047650
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Molano A;Huang Z;Marko MG;Azzi A;Wu D;Wang E;Kelly SL;Merrill AH Jr;Bunnell SC;Meydani SN
• 通讯作者: Meydani SN

Vitamin E and aging immune response.

维生素 E 和衰老免疫反应。

• 发表时间: 1995
• 期刊: Clinics in geriatric medicine.
• 作者: Meydani,SN;Hayek,MG
• 通讯作者: Hayek,MG

Mechanism of age-associated up-regulation in macrophage PGE2 synthesis.

巨噬细胞 PGE2 合成中年龄相关上调的机制。

• DOI: 10.1016/j.bbi.2004.05.003
• 发表时间: 2004
• 期刊: Brain, behavior, and immunity.
• 作者: Wu,Dayong;Meydani,SiminNikbin
• 通讯作者: Meydani,SiminNikbin

Enhanced expression of inducible cyclooxygenase with age in murine macrophages.

小鼠巨噬细胞中诱导型环氧合酶的表达随着年龄的增长而增强。

• 发表时间: 1997
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Hayek,MG;Mura,C;Wu,D;Beharka,AA;Han,SN;Paulson,KE;Hwang,D;Meydani,SN
• 通讯作者: Meydani,SN

Vitamin E reverses impaired linker for activation of T cells activation in T cells from aged C57BL/6 mice.

维生素 E 可逆转老年 C57BL/6 小鼠 T 细胞中受损的 T 细胞激活连接子。

• DOI: 10.3945/jn.108.103416
• 发表时间: 2009
• 期刊: The Journal of nutrition
• 作者: Marko,MelissaG;Pang,Hoan-JenE;Ren,Zhihong;Azzi,Angelo;Huber,BrigitteT;Bunnell,StephenC;Meydani,SiminNikbin
• 通讯作者: Meydani,SiminNikbin