Abstract-Our previous studies have shown that Fc gamma receptor (Fc␥R)-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 Fc␥R triggers activation of signal transduction pathways that alter gene expression in macrophages. In this study, we determined whether engagement of Fc␥R 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 Fc␥R 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. n recent years, circulating autoantibodies against modified forms of LDL and immune complexes containing modified LDL have been detected in diabetic and nondiabetic subjects, with and without coronary artery disease, by our and other research groups. 1-5 Several lines of evidence suggest that autoantibodies against oxidized LDL (oxLDL) and the immune complexes formed by the association of these autoantibodies with oxLDL (oxLDL-ICs) play an important role in the development of atherosclerosis: (1) a correlation between the titer of autoantibodies to oxLDL and the rate of progression of atherosclerosis has been shown to be statistically significant 3 ; (2) both anti-oxLDL autoantibodies and oxLDLICs have been detected in human atherosclerotic plaques 6 ; and (3) it has been shown that uptake of immune complexes containing either native or oxidized LDL by macrophages through type I Fc gamma receptor (Fc␥RI) led to the transformation of macrophages into foam cells 7-10 and to their activation. 11 Activation of macrophages by oxLDL-IC, in turn, results in increased cytokine release of, for example, tumor necrosis factor ␣ (TNF␣) and interleukin-1 (IL-1), and enhanced respiratory burst. 11 It has been shown that TNF␣ and IL-1 have a considerable impact in the development of atherosclerosis. [12][13][14] In our previous studies investigating the mechanisms by which LDL...
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