Effects of cytokines on the production of lipoprotein lipase in cultured human macrophages

Macrophages are important cells in the pathogenesis of atherosclerosis because of their tendency to accumulate lipid and become transformed into foam cells. Cultured human monocyte-derived macrophages spontaneously secrete lipoprotein lipase (LPL), and LPL has been linked to increase lipid uptake by these cells. Because secretion of various macrophage products depends on activation by lymphokines, we studied the effects of immunoregulatory lymphokines on LPL secretion by cultured human macrophages. After culturing cells in RPMI 1640 medium with 20% fetal calf serum, recombinant human gamma-interferon (gamma-INF), interleukin-1 (IL-1), and interleukin-2 (IL-2) were added to the medium and LPL secretion was assessed by measuring LPL activity and/or LPL mass in the medium. Gamma-INF suppressed LPL production both when added to freshly plated cultured of human blood monocytes, as well as when added to monocyte/macrophages from mature cultures (day 6) that were producing large amounts of LPL. IL-1 inhibited medium LPL when added to freshly plated cultures, but not when added to mature cultures. On the other hand, IL-2 did not inhibit LPL in freshly plated cultures, but produced a dose-dependent suppression of LPL from mature cultures. None of the cytokines were cytotoxic to macrophages, and cells that were cultured in gamma-INF demonstrated partial recovery from LPL-suppressive doses of the cytokine. After exposure of cells to 50 U/ml of gamma-INF and 50 U/ml of IL-2 for 3 days, LPL mRNA levels, when expressed as LPL/gamma-actin ratios, were 42% and 53% of controls, respectivley. Thus, activation of human macrophages in vitro by gamma-INF resulted in a suppression of LPL production. IL-1 and IL-2 had more complex effects on macrophage LPL, which depended on the timing of cytokine addition.