The major goal of this project is to develop new therapies for rheumatoid arthritis and other human autoimmune diseases through modification of tissue lipid composition. Dietary lipids containing omega-3, or n-3, polyunsaturated fatty acids (PUFA), compared to other fatty acids, reduce the severity of rheumatoid arthritis and other autoimmune diseases in humans and in experimental animals. We propose studies of the mechanisms of the anti-inflammatory effects and immune suppression by n-3 PUFA in order to improve the effectiveness of the therapy of autoimmune diseases using dietary supplements of n-3 PUFA. This project will study the activation of neutrophils and monocytes; cells involved in autoimmune diseases. In order to accomplish the goals of this project, we propose four specific aims: l. Investigate the mechanism of the observed suppressed responsiveness of neutrophils from patients with rheumatoid arthritis compared to normal individuals. Assess how the n-3 PUFA partially enhance the chemotactic responsiveness toward that seen in cells from normal individuals. 2. Determine the mechanisms of the marked inhibition of rheumatic responsiveness of neutrophils from normal individuals by dietary n-3 PUFA. Initial work has demonstrated that trans-membrane signal transduction is impaired, based on suppressed generation of inositol phosphate second messengers, and future work will determine whether the site of inhibition is proximal or distal to the 6-protein on the chemotaxin-induced pathway. 3. Investigate the mechanism of suppression of monocyte-derived cytokines by n-3 PUFA. These studies will extend preliminary results that indicate suppression of IL-1 gene transcription by n-3 PUFA in murine and human cells. 4. Further characterize the alleviation of murine autoimmune disease by n- 3 PUFA. The effects of n-3 PUFA in plant and marine sources will be compared. The results of these experiments will lead to better understanding of the mechanisms of the anti-inflammatory effects of n-3 PUFA on autoimmune disease. More knowledge of these mechanisms should promote better application of dietary n-3 PUFA in the prevention and therapy of human auto- immune diseases.
