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Vol. 14, Issue 10, 4196-4206, October 2003

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Actin Polymerization in Macrophages in Response to Oxidized LDL and Apoptotic Cells: Role of 12/15-Lipoxygenase and Phosphoinositide 3-Kinase

Yury I. Miller ^* , Dorothy S. Worrall ^*, Colin D. Funk , James R. Feramisco , and Joseph L. Witztum ^*

^* Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California 92093; Cancer Center, University of California, San Diego, La Jolla, California 92093; and Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Submitted February 4, 2003; Revised May 15, 2003; Accepted June 2, 2003
Monitoring Editor: David Drubin

Formation of filamentous F-actin drives many cellular processes, including phagocytosis and cell spreading. We have recently reported that mouse macrophage 12/15-lipoxygenase (12/15-LO) activity promotes F-actin formation in filopodia during phagocytosis of apoptotic cells. Oxidized low-density lipoprotein (OxLDL) also stimulates robust F-actin formation and spreading of macrophages. However, unlike apoptotic cells, OxLDL did not cause specific translocation of 12/15-LO to the cell membrane, neither in macrophages nor in GFP-15LO–transfected COS-7 cells. Moreover, inhibition of 12/15-LO activity in macrophages by a specific inhibitor or by 12/15-LO gene disruption did not affect OxLDL-induced actin polymerization. Among LDL modifications modeling OxLDL, LDL modified by incubation with 15LO-overexpressing fibroblasts was as active in eliciting F-actin response as was OxLDL. This LDL modification is well known to produce minimally modified LDL (mmLDL), which is bioactive and carries lipid oxidation products similar to those produced by 12/15-LO catalysis. MmLDL activated phosphoinositide 3-kinase (PI3K), and PI3K inhibitors abolished mmLDL-induced macrophage spreading. We hypothesize that OxLDL and mmLDL may contribute oxidized lipids to the macrophage cell membrane and thereby mimic intracellular 12/15-LO activity, which leads to uncontrolled actin polymerization and dramatic cytoskeletal changes in macrophages.

Online version of this article contains video material. Online version is available at www.molbiolcell.org.

Corresponding author. E-mail address: yumiller{at}ucsd.edu.

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