OXIDANT STRESS, EICOSANOIDS, AND IMMUNE FUNCTIONS

作为我们对潜在的分子机制的持续兴趣的一部分， 维生素E和硒的抗氧化防御功能，我们将 对膳食维生素E和硒的作用进行了详细的调查， 状态可影响前列腺素（PG）和白三烯（LT）生物合成 在与免疫系统相关的细胞中， 类二十烷酸的合成涉及许多关键的 单核细胞活性，包括信号转导、细胞因子 生产和细胞增殖。 这些假设是基于 前提是维生素E和硒可以调节PGs和LTs的合成。 维生素E是一种自由基清除剂和硒依赖性谷胱甘肽 过氧化物酶（Se-GSH-Px）是参与酶系统的关键组分， 减少脂肪酸氢过氧化物（FAHPs）。 这些微量营养素 可以控制类花生酸的生物合成，因为自由基和FAHP 环氧合酶和脂氧合酶的先决条件，关键酶参与 PG和LT生物合成中限速步骤的催化， 分别 将使用喂食饮食的C57 BL/6 J小鼠进行拟定实验 补充或缺乏维生素E、Se或两者。 具体 目的是：1）确定膳食维生素E和/或硒的后果 巨噬细胞和淋巴细胞中PG和LT水平缺乏; 2） 评估类花生酸生物合成之间的潜在关系， 生物反应调节剂的产生， 维生素E和/或硒缺乏时单核细胞的能力; 3)研究维生素E和/或硒缺乏对 白细胞介素-2和转铁蛋白受体在细胞表面的表达 单核细胞;和4）检查之间的潜在关系 类花生酸的产生和细胞内信号传导和增殖 维生素E和/或硒缺乏状态的淋巴细胞。 Molecular Probes 将被用来确定是否维生素E不足的影响 和/或硒营养对细胞因子产生、一氧化氮水平和 受体表达是在翻译或转录水平。 设计了额外的实验来研究可能 解释细胞增殖和细胞毒性能力的降低 单核细胞缺乏维生素E和/或硒。 结果进行 这些研究将促进我们对氧化应激影响的理解， 例如在维生素E和/或硒缺乏状态中发现，对重要的 宿主防御机制，并将提供分子基础的作用， 类花生酸对基本免疫细胞功能的影响。

As a part of our continuing interest in the molecular mechanisms underlying the antioxidant defense functions of vitamin E and selenium (Se), we will undertake a detailed investigation into the role dietary vitamin E and Se status can influence prostaglandin (PG) and leukotriene (LT) biosynthesis in cells associated with the immune system, and that this altered eicosanoid synthesis is involved in the impairment of a number of critical mononuclear cell activities including signal transduction, cytokine production, and cell proliferation. These hypotheses are based on the premise that vitamin E and Se can modulate the synthesis of PGs and LTs. Vitamin E is a free radical scavenger and Se-dependent glutathione peroxidase (Se-GSH-Px) is a key component of an enzyme system involved in the reduction of fatty acid hydroperoxides (FAHPs). These micronutrients can control eicosanoid biosynthesis because free radicals and FAHPs are prerequisites for cyclooxygenase and lipoxygenase, key enzymes involved in the catalysis of rate-limiting steps in PG and LT biosynthesis, respectively. The proposed experiments will be conducted using C57BL/6J mice fed on diets supplemented with or deficient in vitamin E, Se, or both. The specific aims are: 1) to determine the consequences of dietary vitamin E and/or Se deficiency on PG and LT levels in macrophages and lymphocytes; 2) to evaluate the potential relationships between eicosanoid biosynthesis, biological response modifier production, and altered functional capabilities of mononuclear cells during vitamin E and/or Se deficiencies; 3) to examine the effects of vitamin E and/or Se deficiencey on interleukin-2 and transferrin receptor expression on the surface of mononuclear cells; and 4) to examine the potential relationships between eicosanoid production and intracellular signalling and proliferation by lymphocytes in vitamin E and/or Se deficiency states. Molecular probes will be employed to determine whether the effects of inadequate vitamin E and/or Se nutrition on cytokine production, nitric oxide levels, and receptor expression are at the translational or transcriptional levels. Additional experiments are designed to investigate the mechanisms that may explain the decreased proliferative and cytotoxic capabilities of mononuclear cells by vitamin E and/or Se deficiency. Results of these studies will advance our understanding of the influence of oxidant stress, such as that found in vitamin E and/or Se deficient states, on important host defense mechanisms and will provide a molecular basis for the role of eicosanoids on essential immune cell functions.