Lipid requirements for leukocyte chemotaxis and phagocytosis: effects of inhibitors of phospholipid and cholesterol synthesis.

Leukocyte chemotaxis and phagocytosis are accompanied by alterations in the morphology of the cellular plasma membrane, suggesting that modification of membrane composition or synthesis might be required for these biologic activities. We therefore determined whether the synthesis or utilization of the major lipid components of membranes, cholesterol, and/or phospholipids was required for leukocyte chemotaxis and phagocytosis. The antilipidemic drugs, clofibrate and triparanol, were tested for their effects on the chemotaxis and phagocytosis of different types of leukocytes. Clofibrate, an inhibitor of phospholipid and cholesterol synthesis, inhibited the chemotaxis of human monocytes and guinea pig peritoneal macrophages by >95%. The dose that produced a 50% inhibition (ID50) of macrophage chemotaxis correlated well with the ID50 for inhibition of phospholipid synthesis. Administration of clofibrate to mice depressed macrophage accumulation in vivo in response to an i.p. injection of an inflammmatory stimulus. The incubation of monocytes or macrophages with the inhibitor of cholesterol synthesis, triparanol, also inhibited the chemotaxis of these cells by >95%. The ID50 for inhibition of chemotaxis was identical to the ID50 for inhibition of cholesterol synthesis. The inhibition of chemotaxis by triparanol but not by clofibrate could be reversed by incubation of cells with the low-density lipoprotein fraction from human plasma, indicating that triparanol inhibited chemotaxis by curtailing cholesterol synthesis. The chemotaxis of human polymorphonuclear leukocytes was also markedly decreased by triparanol but was much less sensitive to treatment with clofibrate when compared to monocyte and macrophage chemotaxis. Phagocytosis by human monocytes and guinea pig macrophages was also less sensitive to treatment with clofibrate unless a large quantity of material was to be ingested. These findings suggest that chemotaxis and, under some conditions, phagocytosis require new membrane synthesis and/or modification of the cholesterol: phospholipid ratios in cellular membrane.