循環中陰電性低密度脂蛋白透過LOX-1及活化NF-κB、ERK2和JNK在巨噬細胞中引起G-CSF 和GM-CSF表現

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Hypercholesterolemia promotes the formation of atherosclerotic lesions in which oxidized LDL (oxLDL) and monocyte-derived macrophages are frequently found. It is generally believed that oxLDL is recognized and internalized by macrophages via scavenger receptors and resulted in lipid accumulation and inflammation. Results of several studies indicate the presence of neutrophils and neutrophil-derived mediators in atherosclerotic lesions, which is accompanied with higher serum granulocyte colony-stimulating factor (G-CSF), a critical mediator to increase neutrophils and recruitment of neutrophils to inflammatory sites. Moreover, granulocyte macrophage colony-stimulating factor (GM-CSF), a critical regulator of intimal cell proliferation in early atherosclerotic lesions, is also expressed in atherosclerotic lesions. Animal studies showed that treatment with either G-CSF or GM-CSF enhances the progression of atherosclerosis. These results suggest that G-CSF and GM-CSF play important roles in the progression of atherosclerosis. However, if expression of G-CSF and GM-CSF were induced by oxLDL is unknown. In this study, we investigated if native LDL, naturally occurring electronegative LDL (LDL(-)) and Cu+2-induced oxLDL were able to induce G-CSF and GM-CSF expression in human macrophages. The LDL(-) was isolated from plasma of high-fat/cholesterol fed New Zealand rabbits or patients with acute myocardial infarction by ion exchange chromatography. We found that LDL(-) remarkably promoted G-CSF and GM-CSF expression and secretion in THP-1-derived macrophages in a time- and dose-dependent manner; while native LDL and Cu+2-induced oxLDL exert much lower effects. LDL(-)-induced G-CSF and GM-CSF expession were almost abolished in LOX-1 knock-down cells. Using pharmaceutical vii inhibitors and shRNA knockdown strategies, our results demonstrate that induction of G-CSF and GM-CSF by LDL(-) required activation of NF-κB, ERK2 and JNK. However, LDL(-)-induced G-CSF and GM-CSF production was not inhibited by cytochalasin D, an inhibitor of endocytosis, suggesting that LDL(-)-induced signal transduction may not dependent on receptor-mediated endocytosis. However, the possibility requires further investigation. Incubation with HDL partially decreased LDL(-)-induced expression of G-CSF, GM-CSF, TNF-α and IL-1β. Taken together, our results show that LDL(-) induces G-CSF and GM-CSF expression via LOX-1 and through activation of NF-κB, ERK2 and JNK signaling pathway in THP-1-derived macrophages. All these effects of LDL(-) might generate before endocytosis. These results suggest that LDL(-) is an important modulator of G-CSF and GM-CSF expression that further link between LDL(-) and atherosclerosis.