Abstract
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 increased 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 cultures 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, respectively. Thus, activation of human macrophages in vitro by gamma-INF resulted in a suppression of LPL production.(ABSTRACT TRUNCATED AT 250 WORDS)
Highlights
Macrophages are important cells in the pathogenesis of atherosclerosis because of their tendency to accumulate lipid and become transformed into foam cells
In addition to providing lipid substrate to muscle and adipose tissue, lipoprotein lipase (LPL) is secreted by human monocyte-derived macrophages in culture [1, 2], which leads to increased lipid uptake by these cells
These studies demonstrated that the addition of gamma-INF to macrophages in vitro resulted in a marked suppression of LPL production by these cells, whereas IL-1 and IL-2 had effects on LPL that depended on when they were added to the cultures
Summary
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 increased lipid uptake by these cells. Lymphokines such as interleukin-2 (IL-2) and gamma-interferon (gamma-INF) are secretory products of activated lymphocytes and are known to regulate monocyte/macrophage function as well It is not known whether cytokine-mediated regulation of macrophage function is important in the development of atherosclerosis. Lymphokines (IL-2, and gamma-INF) produced by activated lymphocytes, and IL-1, a cytokine produced by activated monocyte/macrophages These studies demonstrated that the addition of gamma-INF to macrophages in vitro resulted in a marked suppression of LPL production by these cells, whereas IL-1 and IL-2 had effects on LPL that depended on when they were added to the cultures
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