Regulation of lymphocyte proliferation by cholesterol: the role of endogenous sterol metabolism and low density lipoprotein receptors.
Cholesterol availability is a major determinant of the capacity of lymphocytes to proliferate. Either endogenously-synthesized cholesterol or that taken up from the medium can be utilized as a source for new membrane biosynthesis. Mitogenic stimulation of human lymphocytes augments the rate of endogenous sterol synthesis. This mitogen-induced increase in lymphocyte sterol synthesis can be observed within 4 h of stimulation and is prevented by suppressing the activity of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase with the specific inhibitors ML-236B or mevinolin. The resultant inhibition of lymphocyte sterol synthesis does not affect mitogen-stimulated blast transformation or initial entry into the S phase of the cell cycle, even when no source of exogenous sterol is present. However, maximal enlargement of the stimulated blast cells is suppressed by inhibition of HMG-CoA reductase activity, and lymphocyte proliferation is completely prevented. These inhibitory effects are reversed by the addition either of mevalonate, the product of the inhibited enzyme, or of low-density-lipoprotein (LDL) cholesterol. The finding that LDL cholesterol could not support growth of lymphocytes obtained from individuals who lacked LDL receptors indicates that LDL-mediated delivery of exogenous sterols to proliferating lymphocytes requires intact LDL receptors. The data indicate that neither endogenous sterol synthesis nor a source of cholesterol is necessary for mitogen-stimulated activation and blast transformation of human lymphocytes. Subsequent enlargement and cell division requires either sterol synthesis or an exogenous source of cholesterol. When the exogenous source of cholesterol is in the form of LDL, normal LDL receptors are also necessary.
Cuthbert
J A
JA
Department of Internal Medicine, University of Texas Health Science Center, Southwestern Medical School, Dallas 75235.
Lipsky
P E
PE
D002453:Cell Cycle; D002469:Cell Separation; D002478:Cells, Cultured; D002784:Cholesterol / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008214:Lymphocytes / Q000201:enzymology / Q000502:physiology / Q000648:ultrastructure; D010835:Phytohemagglutinins / Q000494:pharmacology; D011973:Receptors, LDL / Q000378:metabolism* / Q000502:physiology; D013261:Sterols / Q000096:biosynthesis / Q000378:metabolism*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010835:Phytohemagglutinins; D011973:Receptors, LDL; D013261:Sterols; C012258:mevastatin; D002784:Cholesterol; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases