The proposed research will investigate the role of sterol metabolism in the growth and function of lymphocytes and monocytes. Lipoproteins and oxygenated sterols modify rates of endogenous sterol synthesis in many cell types in vitro including human peripheral blood mononuclear cells. Additionally, lipoproteins and polar lipids may regulate immune responses in vivo by modulating lymphocyte and monocyte-macrophage functions. Cultured human peripheral blood mononuclear cells will be used as a model system to study the role of sterol metabolism in various activities of these cells including lymphocyte activation and proliferation, and monocyte functions. Sterol synthesis will be inhibited with ML-236B or oxygenated sterols and mitogen-induced responses assayed by measurement of 1) (3H)precursor uptake, 2) blast transformation and membrane systhesis from changes in cell volume, 3) intracellular DNA content, and 4) actual cell proliferation. The effect of initial sterol depletion will be examined as well as the capacity of exogenous sterols to substitute for de nova synthesis. Human monocytes will also be studied to explore the relationship of cholesterol metabolism to processes requiring rapid membrane turnover such as pinocytosis and phagocytosis. The possibility that these functions and others such as chemotaxis and glass adherence might be altered by inhibition of sterol synthesis will be examined. Furthermore, the effect of activation on the endogenous rate of sterol synthesis by monocytes will be investigated. The effect of modifying exogenous and endogenous sterols on the generation of antibody-forming cells will also be determined and the relative effects on T cells, B cells and monocytes in this system will be assessed. These studies should provide additional insight not only into the regulation of sterol synthesis in these various cells in vitro but also into the potential role of sterol metabolism in regulating the immune response.
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