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J. Biol. Chem., Vol. 281, Issue 23, 15757-15762, June 9, 2006

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Constitutive Receptor-independent Low Density Lipoprotein Uptake and Cholesterol Accumulation by Macrophages Differentiated from Human Monocytes with Macrophage-Colony-stimulating Factor (M-CSF)^*

Bin Zhao, Yifu Li, Chiara Buono, Stephen W. Waldo, Nancy L. Jones, Masahiro Mori, and Howard S. Kruth¹

From the Section of Experimental Atherosclerosis, NHLBI, National Institutes of Health, Bethesda, Maryland 20892-1422 and the Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1092

Recently, we have shown that macrophage uptake of low density lipoprotein (LDL) and cholesterol accumulation can occur by nonreceptor mediated fluid-phase macropinocytosis when macrophages are differentiated from human monocytes in human serum and the macrophages are activated by stimulation of protein kinase C (Kruth, H. S., Jones, N. L., Huang, W., Zhao, B., Ishii, I., Chang, J., Combs, C. A., Malide, D., and Zhang, W. Y. (2005) J. Biol. Chem. 280, 2352–2360). Differentiation of human monocytes in human serum produces a distinct macrophage phenotype. In this study, we examined the effect on LDL uptake of an alternative macrophage differentiation phenotype. Differentiation of macrophages from human monocytes in fetal bovine serum with macrophage-colony-stimulating factor (M-CSF) produced a macrophage phenotype demonstrating constitutive fluid-phase uptake of native LDL leading to macrophage cholesterol accumulation. Fluid-phase endocytosis of LDL by M-CSF human macrophages showed non-saturable uptake of LDL that did not down-regulate over 48 h. LDL uptake was mediated by continuous actin-dependent macropinocytosis of LDL by these M-CSF-differentiated macrophages. M-CSF is a cytokine present within atherosclerotic lesions. Thus, macropinocytosis of LDL by macrophages differentiated from monocytes under the influence of M-CSF is a plausible mechanism to account for macrophage foam cell formation in atherosclerotic lesions. This mechanism of macrophage foam cell formation does not depend on LDL modification or macrophage receptors.

Received for publication, September 30, 2005 , and in revised form, April 10, 2006.

^* This work was supported in part by the Intramural Research Program of the National Institutes of Health (NIH)/NHLBI, by NIH Grant HL-41990 (to N. L. J.), and by the Howard Hughes Medical Institute-NIH Medical Research Scholar Program (to S. W. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains a movie.

¹ To whom correspondence should be addressed: Section of Experimental Atherosclerosis, NHLBI, National Institutes of Health, Bldg. 10, Rm. 5N-113, 10 Center Dr. MSC 1422, Bethesda, MD 20892-1422. Tel.: 301-496-4826; Fax: 301-402-4359; E-mail: kruthh{at}nhlbi.nih.gov.

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