Aging Vitamin E, and Immune Function in Aged

描述(由申请人提供)：衰老与T细胞介导的功能下降有关，这导致传染病和肿瘤的发病率、发病率和死亡率更高。T细胞的年龄相关性缺陷被证明是由于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，PGE2产量的增加是由于神经酰胺介导的环氧合酶2(COX-2)转录上调，COX-2是PGE2合成的关键调节酶。然而，神经酰胺上调COX-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，补充维生素E(E)通过两种不同的机制来改善T细胞介导的功能：a)通过减少PGE2的产生，从而减少巨噬细胞Mphi介导的抑制；b)通过直接增强T细胞的功能，而不依赖于其对Mphi PGE2产生的影响。E通过提高老年小鼠幼稚T细胞产生IL-2和细胞分裂周期的能力来发挥作用。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)探讨神经酰胺诱导老年Mphi环氧合酶-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上调老年巨噬细胞COX-2表达的假设，这是通过增强PKC-Zeta活性，导致IkappaB磷酸化增加，从而降解。这反过来会增加NFkappaB的激活和COX-2的表达。 2)探讨E诱导老年幼稚T细胞功能增强的机制。为了实现这一目标，我们将检验这一假设，即E通过提高老年小鼠在T细胞受体(TCR)和抗原接触部位形成有效免疫突触的能力来增强幼稚T细胞的功能。这反过来将导致改善TCR相关的信号转导，并随后在老年小鼠中产生IL-2。我们认为，E通过改变TCR相关的关键信号分子在膜脂筏中的重新分布来诱导其作用，其机制如下：a)增加与TCR介导的激活相关的关键信号分子的棕榈酰化；b)改变脂筏脂组分的结构。 这些实验将阐明与年龄相关的巨噬细胞和T细胞调节失调的机制，以及E对它们的正常化。这反过来将有助于设计实际的营养干预措施，以逆转和/或延缓与年龄相关的免疫和炎症反应以及与之相关的疾病的调节失调。

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.