The overall object of this proposal is to investigate biochemical and molecular mechanisms through which gammalinolenic acid (GLA), dihomogammalinolenic acid (DGLA), and other unsaturated fatty acids influence T lymphocytes and monocytes contribute to propagation of joint tissue injury in patients with rheumatoid arthritis (RA). Administration of GLA suppresses joint pain and swelling in RA patients with active synovitis. The means whereby GLA, DGLA and other unsaturated fatty acids influence transduction of activation signals from the cell surface to the nucleus to effect changes in gene expression will be phosphorylation events, on phospholipase C activity and phosphorylation, and on phosphorylation facilitated by protein kinase C will be examined. Effects of the fatty acids on regulation in monocytes of the mediator of inflammation interleukin-1 beta will be investigated in vitro and in vivo; studies will include determinations of interleukin-1 converting enzyme, the interleukin receptors, and the interleukin-1 receptor antagonist. Analysis of cellular fatty acids and their distribution in lipid classes will be correlated with cell function studied. These experiments should help define mechanisms of signal transduction in activated lymphocytes and monocytes, and provide a greater understanding of the cellular and molecular basis for the immunomodulatory effects of unsaturated fatty acids. Results of these studies may lead to more rational use of fatty acids in the treatment of diseases characterized by disordered immune responses, acute and chronic inflammation, and tissue injury.
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