Suppression of endothelial or lipoprotein lipase in THP-1 macrophages attenuates proinflammatory cytokine secretion

Abstract

LPL and endothelial lipase (EL) are associated with macrophages in human atherosclerotic lesions, and overexpression of LPL in mouse macrophages is associated with a greater extent of atherosclerosis. To investigate potential mechanisms by which macrophage-derived lipase expression may mediate proatherogenic effects, we used lentivirus-mediated RNA interference to suppress the expression of either LPL or EL within THP-1 macrophages. After suppression of either LPL or EL, significant decreases in the concentration of interleukin-1b, interleukin-6, monocyte chemoattractant protein-1, and tumor necrosis factor-a were observed. Incubation of THP-1 macrophages with either mildly or extensively oxidized LDL consistently decreased cytokine expression, which was additive to that contributed by lipase suppression. Decreased lipase expression was also associated with an altered lipid composition, with reduced percentages of cholesterol (unesterified and esterified), triglycerides, and lysophosphatidylcholine. Microarray data indicated a decreased expression of proinflammatory genes, growth factors, and antiapoptotic genes. By contrast, there was an increased expression of lipoprotein receptors (scavenger receptor 1, low density lipoprotein receptor, scavenger receptor class B type I, and CD36). Thus, we conclude that the suppression of either LPL or EL decreases proinflammatory cytokine expression and influences the lipid composition of THP-1 macrophages. These results provide further insight into the specific metabolic and potential pathological roles of LPL and EL in human macrophages.-Qiu, G., A. C. Ho, W. Yu, and J. S. Hill. Suppression of endothelial or lipoprotein lipase in THP-1 macrophages attenuates proinflammatory cytokine secretion. J. Lipid Res. 2007. 48: 385-394.

Targeted deletion of endothelial lipase increases HDL particles with anti-inflammatory properties both in vitro and in vivo

“…It has been reported that suppression of EL in macrophages directly decreases the secretion of infl ammatory cytokine secretion ( 28,29 ). In the present study, however, there was no difference in TNF-␣ production by isolated macrophages between EL Ϫ / Ϫ and WT mice.…”

MicroRNA-29a regulates pro-inflammatory cytokine secretion and scavenger receptor expression by targeting LPL in oxLDL-stimulated dendritic cells

“…At the same time, after suppression of LPL, significantly increased expressions of lipoprotein receptors [31] were observed. Therefore, the expression of scavenger receptors was measured to demonstrate the effect of miR-29a on oxLDLmediated DCs lipid uptake.…”

“…In contrast, oxLDL-mediated DCs pro-inflammatory cytokines secretion is exacerbated after downregulation of miR-29a expression. Previously, Qiu G et al [31] showed that LPL suppression causes decreased expression of pro-inflammatory cytokines. Accordingly, downregulation of LPL through miR-29a overexpression and LPL inhibition with siRNA have similar effects.…”

Glycosylation of endothelial lipase at asparagine-116 reduces activity and the hydrolysis of native lipoproteins in vitro and in vivo

“…Thus, the presence of N-linked glycosylation at Asn-116 of EL may have evolved in its divergence from LPL, in part as a means to direct greater specificity of EL in vivo away from apolipoprotein B-containing lipoproteins and toward HDL. EL activity on HDL has been shown to have several effects, including enhanced adenosine triphosphate binding cassette transporter A1-mediated cholesterol efflux capacity of plasma (29), increased cholesteryl ester selective uptake (30), increased peroxisome proliferator-activated receptor a signaling in endothelial cells (31), and altered macrophage inflammatory responses (32). Of note, HL also acts on HDL but prefers larger TG-rich HDL 2 particles (33).…”