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(Circulation Research. 2007;100:1008.)
© 2007 American Heart Association, Inc.

Molecular Medicine

Upregulation of Macrophage Endothelial Lipase by Toll-Like Receptors 4 and 3 Modulates Macrophage Interleukin-10 and -12 Production

Xun Wang, Weijun Jin, Daniel J. Rader

From the Institute for Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia.

Correspondence to Dr Daniel J. Rader, University of Pennsylvania School of Medicine, Center for Experimental Therapeutics, 421 Curie Blvd, 654 BRBII/III Labs, Philadelphia, PA 19104-6160. E-mail rader{at}mail.med.upenn.edu

Limited data suggest that endothelial lipase (EL) is synthesized not only by endothelial cells but also by macrophages. Previous studies showed that proinflammatory cytokines upregulate EL in endothelial cells, but there are very few data regarding EL expression, regulation, and functional consequences in macrophages. In the present study, RAW cells and mouse peritoneal macrophages were treated with Toll-like receptor (TLR) ligands and EL expression and its consequences were assessed. We demonstrate that lipopolysaccharide, a TLR4 ligand; and polyinosinic:polycytidylic acid (poly I:C), a TLR3 ligand; but not lipoteichoic acid, a TLR2 ligand, upregulate macrophage EL expression both ex vivo and in vivo. In contrast, macrophage lipoprotein lipase expression is significantly repressed by lipopolysaccharide or poly I:C. Using C3HJ and TLR3 knockout mice, we further show that upregulation of macrophage EL expression by lipopolysaccharide or poly I:C is TLR4 or TLR3 dependent, respectively. Furthermore, we demonstrate that lipopolysaccharide induced interleukin (IL)-10 production was significantly reduced, whereas IL-12 production is significantly increased in J744 macrophages and mouse peritoneal macrophages overexpressing human EL. Conversely, significantly increased IL-10 and significantly decreased IL-12 expression were observed in mouse peritoneal macrophages isolated from EL knockout mice. Finally we show that the catalytic activity is required for EL to modulate the balance of macrophage IL-10 and IL-12 production. These results suggest that macrophage EL may play important roles in modulating the macrophage inflammatory response through local hydrolysis of HDL.

Key Words: endothelial lipase • macrophage • inflammation • TLR • cytokines

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