OXIDANT STRESS, EICOSANOIDS, AND IMMUNE FUNCTIONS

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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.