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.