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Inhibition by Membrane-bound Low-Density Lipoproteins of the Primary Inductive Events of Mitogen-stimulated Lymphocyte Activation¹

Chemistry Department, Indiana University, Bloomington, Indiana 47405

Low-density lipoproteins (LDL) inhibit phytohemagglutinin (PHA)-enhanced accumulation of calcium ion and cyclic guanosine 3':5'-monophosphate, and phosphatidylinositol turnover in human lymphocytes. Inhibition by LDL of PHA-induced ³²P incorporation into monophosphoinositide and cyclic guanosine 3':5'-monophosphate accumulation correlates directly with inhibition by LDL of calcium ion accumulation. These results suggest that calcium ion accumulation is required for PHA to direct turnover of monophosphoinositide and cyclic guanosine 3':5'-monophosphate synthesis in lymphocytes and that inhibition of this mitogen-induced response by LDL may be a direct consequence of the ability of these lipoproteins to prevent calcium ion accumulation by the activated cells. The ability of LDL to suppress PHA-enhanced calcium ion accumulation is directly proportional to the amount of LDL localized at the cell surface, indicating that internalization of the lipoproteins is not required for immunoregulation. This conclusion is supported by two additional lines of evidence: (a) LDL depleted of the bioregulatory constituent cholesterol are as effective as are native LDL in suppressing lymphocyte response to PHA; and (b) LDL-Sepharose complexes which cannot be endocytosed by the cells are as immunosuppressive as soluble LDL. The data clearly establish that membrane-bound LDL may have a regulatory role.

¹ Presented at the Workshop on Fat and Cancer, December 10 to 12, 1979, Bethesda, Md. This research was supported by USPHS Grant HL 20882 from NIH and by Grant 79-1072 from the American Heart Association.

² Presented address: Department of Biological Chemistry, University of Cincinnati College of Medicine, 231 Bethesda Ave., Cincinnati, Ohio 45267. To whom requests for reprints should be addressed.

³ Recipient of USPHS Traineeship GM07227 in Molecular and Cellular Biology.