Stress and Proinflammatory Cytokines: Omega-3 Intervention

描述（由申请人提供）：促炎细胞因子影响许多年龄相关疾病的发病和病程。压力和抑郁可以大大提高促炎细胞因子的产生。饮食也会影响这些细胞因子的合成。花生四烯酸（AA）衍生的（omega-6或n-6）类二十烷酸（主要来自精制植物油，如玉米、向日葵和红花）增加了这些细胞因子的产生。相反，在鱼类、鱼油、核桃和亚麻籽产品中发现的omega-3 （n-3）多不饱和脂肪酸（PUFAs）可以抑制aa衍生的二十烷酸的产生。因此，较高的n-6:n-3比率促进促炎细胞因子的产生。重要的是，高n-6:n-3比率预示着压力时期细胞因子的增加，以及更高水平的抑郁症状。此外,NF - ?B活化是上调促炎细胞因子产生的主要途径；心理压力促进NF-？而n-3 PUFAs可降低NF-？B激活。因此，我们将研究压力和饮食如何相互作用，以影响60医学生的免疫功能和情绪。该设计将是一项双盲、安慰剂对照、随机临床试验，为期3个月。血液样本用于监测脂肪酸的变化以及免疫和心理数据将在低压力或非检查基线（时间1）和检查的早晨（时间2）再次收集。接下来的四个时间点将提供一个机会，看看补充剂如何影响随后的低压力和高压力时期的反应。时间4将在开始补充后大约6周收集样本，而时间6将在补充后3个月收集样本，提供有关变化动力学的数据。具体目的：(1)确定补充n-3 PUFA是否会降低NF-？B活化，以及促炎细胞因子的产生；评估补充后这些变化的时间进程；(2)确定与安慰剂相比，n-3 PUFA补充后是否存在可靠的情绪变化（抑郁、焦虑症状和愤怒）；(3)评估补充n-3 PUFA对学业考试期间细胞因子产生和情绪的典型应激相关增加的调节程度；(4)将外周血单个核细胞（PBMC） n-3 PUFA含量变化作为连续测量的统计分析的效用与单纯使用n-3 PUFA补充剂与安慰剂的统计分析的效用进行比较。虽然行为对免疫功能的影响已被广泛认识，但在饮食影响的背景下，压力和免疫功能是如何相互作用的，我们知之甚少。该研究结合了精神神经免疫学和营养神经科学领域的研究成果，强调了饮食如何增强或抑制与压力相关的免疫变化，从而对应激、脂肪酸和免疫功能的研究做出了贡献。

DESCRIPTION (provided by applicant): Proinflammatory cytokines influence the onset and course of a number of age-associated diseases. Stress and depression can substantially enhance the production of proinflammatory cytokines. Diet also influences the synthesis of these cytokines. Arachidonic acid (AA) derived (omega-6 or n-6) eicosanoids (primarily from refined vegetable oils such as corn, sunflower, and safflower) increase the production of these cytokines. In contrast, the omega-3 (n-3) polyunsaturated fatty acids (PUFAs), found in fish, fish oil, walnuts, and flax seed products, can curb the production of AA-derived eicosanoids. Thus, higher n-6:n-3 ratios promote proinflammatory cytokine production. Importantly, high n-6:n-3 ratios predict greater increases in cytokines during stressful periods, as well as higher levels of depressive symptoms. Furthermore, NF-?B activation is a prime pathway for up-regulating proinflammatory cytokine production; psychological stress promotes NF-?B activation, while n-3 PUFAs can decrease NF-?B activation. Accordingly, we will examine how stress and diet interact to influence immune function and mood in 60 medical students. The design will be a double-blind, placebo-controlled, randomized clinical trial with supplementation over a 3-month period. Blood samples to monitor changes in fatty acids as well as immunological and psychological data will be collected at a lower- stress or non-exam baseline (time 1) and again on the morning of an exam (time 2). The next four time points will provide an opportunity to see how supplementation will affect responses during subsequent lower and higher stress periods. The time 4 sample will be collected approximately 6 weeks after supplementation has been initiated, while the time 6 sample will be collected 3 months after supplementation, providing data on the kinetics of change. Specific aims: (1) To determine if n-3 PUFA supplementation will decrease NF-?B activation, as well as proinflammatory cytokine production; to evaluate the time course for these changes following supplementation; (2) to determine if there are reliable changes in mood (depressive and anxiety symptoms, and anger) following n-3 PUFA supplementation compared to the placebo condition; (3) to assess the extent to which n-3 PUFA supplementation modulates typical stress-related increases in cytokine production and mood during academic examinations; and (4) to compare the utility of statistical analyses that use changes in peripheral blood mononuclear cell (PBMC) n-3 PUFA content as continuous measures with those that simply use n-3 PUFA supplementation vs. placebo. Although behavioral influences on immune function are widely recognized, very little is known about how stress and immune function interact in the context of dietary influences. Bridging the fields of psychoneuroimmunology and nutritional neuroscience, the proposed study would contribute to the literatures on stress, fatty acids, and immune function by highlighting the ways in which diet enhances or inhibits stress-related immune change. Public health relevance: Although behavioral influences on immune function are widely recognized, very little is known about how stress and immune function interact in the context of dietary influences. This placebo-controlled, randomized clinical trial will fill several significant gaps in the literature by addressing the ways in which stress and n-3 PUFA supplementation interact to influence NF-?B activation, proinflammatory cytokine levels, acute inflammatory responses to stress, and mood.