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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI017653-05
Application #
3127330
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1981-05-01
Project End
1986-11-30
Budget Start
1985-05-01
Budget End
1986-11-30
Support Year
5
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Makar, R S; Lipsky, P E; Cuthbert, J A (1998) Sterol-independent, sterol response element-dependent, regulation of low density lipoprotein receptor gene expression. J Lipid Res 39:1647-54
Cuthbert, J A; Lipsky, P E (1995) Suppression of the proliferation of Ras-transformed cells by fluoromevalonate, an inhibitor of mevalonate metabolism. Cancer Res 55:1732-40
Makar, R S; Lipsky, P E; Cuthbert, J A (1994) Non-sterol regulation of low density lipoprotein receptor gene expression in T cells. J Lipid Res 35:1888-95
Spady, D K; Cuthbert, J A (1992) Regulation of hepatic sterol metabolism in the rat. Parallel regulation of activity and mRNA for 7 alpha-hydroxylase but not 3-hydroxy-3-methylglutaryl-coenzyme A reductase or low density lipoprotein receptor. J Biol Chem 267:5584-91
Cuthbert, J A; Lipsky, P E (1991) A product of mevalonate proximal to isoprenoids is the source of both a necessary growth factor and an inhibitor of cell proliferation. Trans Assoc Am Physicians 104:97-106
Cuthbert, J A; Lipsky, P E (1991) Negative regulation of cell proliferation by mevalonate or one of the mevalonate phosphates. J Biol Chem 266:17966-71
Cuthbert, J A; Lipsky, P E (1990) Inhibition by 6-fluoromevalonate demonstrates that mevalonate or one of the mevalonate phosphates is necessary for lymphocyte proliferation. J Biol Chem 265:18568-75
Cuthbert, J A; Lipsky, P E (1990) Tissue-specific regulation of low density lipoprotein receptor gene expression. Trans Assoc Am Physicians 103:271-80
Cuthbert, J A; Lipsky, P E (1990) Mitogenic stimulation alters the regulation of LDL receptor gene expression in human lymphocytes. J Lipid Res 31:2067-78
Cuthbert, J A; Lipsky, P E (1989) Identification of low density lipoprotein receptor abnormalities by assaying functional receptors on proliferating lymphocytes. Arteriosclerosis 9:I43-9

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