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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:1600-1607.)
© 1999 American Heart Association, Inc.

Vascular Biology

Oxidized LDL-Containing Immune Complexes Induce Fc Gamma Receptor I–Mediated Mitogen-Activated Protein Kinase Activation in THP-1 Macrophages

Yan Huang; Ayad Jaffa; Sinikka Koskinen; Akira Takei; Maria F. Lopes-Virella

From the Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, Medical University of South Carolina (Y.H., A.J., S.K., A.T., M.F.L.-V.); and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC.

Correspondence to Maria F. Lopes-Virella, MD, PhD, Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, Medical University of South Carolina, 114 Doughty St, Charleston, SC 29403. E-mail virellam{at}musc.edu

Abstract—Our previous studies have shown that Fc gamma receptor (FcR)-mediated uptake of LDL-containing immune complexes (oxLDL-ICs) by human monocyte-derived macrophages leads to not only transformation of macrophages into foam cells but also macrophage activation and release of cytokines. It has been shown that cross-linking of FcR triggers activation of signal transduction pathways that alter gene expression in macrophages. In this study, we determined whether engagement of FcR by oxLDL-ICs leads to activation of mitogen-activated protein (MAP) kinase pathway, a signaling cascade serving many important functions, including the regulation of gene expression, in THP-1 macrophage-like cells. Our results from immunoblotting, using specific anti-phosphorylated MAP kinase antibodies, showed that oxLDL-ICs induced extracellular signal regulated kinase 2 (ERK2) MAP kinase phosphorylation in THP-1 macrophage-like cells in time- and dose-dependent manners. Cholesterol loading before stimulation led to a longer phosphorylation of ERK2. Nuclear translocation of phosphorylated ERK was markedly increased after the stimulation. Moreover, our data showed that oxLDL-IC induction of MAP kinase was prevented by human monomeric IgG1, suggesting that the specific engagement of type I FcR by oxLDL-IC is responsible for the MAP kinase activation. Finally, we showed that human anti-oxLDL autoantibody-containing immune complexes immobilized on type I collagen induced MAP kinase activation in THP-1 cells. These results strongly suggest that oxLDL-IC, which has been detected in atherosclerotic plaques, may play an important role in macrophage activation and atherogenesis.

Key Words: oxidized LDL • immune complex • mitogen-activated protein kinase • Fc gamma receptor

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