Modulation Of CpG-ODN On Formation Of Macrophage Foam Cell And Related Gene Expression In The Early Stage Of Atherosclerosis

Atherosclerosis, and the resulting coronary heart disease and cerebral stroke, represent the most common cause of death in industrialized nations. Mammalian cells have evolved complex feedback mechanisms to ensure sufficient supply of cholesterol and to prevent its excessive accumulation. During the process of atherosclerosis, these homeostatic mechanisms fail in macrophages. Uncontrolled cholesterol deposition is promoted by scavenger functions of the macrophages and the adaptive mechanisms elicited are not sufficient to process the lipid load. Consequently, a lipid-laden 'foam cell' is formed. The active stages of the lesion of atherosclerosis are characterized by the extensive infiltration of blood-derived monocyte/macrophages through the endothelium into the arterial intima. The migration of monocytes into the arterial intima where they internalize ox-LDL through scavenger receptor and becoming macrophage-derived foam cells results in formation of fatty streaks, .which are believed to represent the earliest type of atherosclerotic plaque.Bacterial DNA contains unmethylated "CpG motifs" that strongly activate the mammalian immune system.The immune effects of synthetic oligodeoxynucleotides (ODN) containing such CpG motifs (CpG DNA) include: induction of B cell proliferation, differentiation, immunoglobulin isotype switching and secretion, and resistance to activation-induced apoptosis; induction of monocyte secretion of IL-12 and other cytokmes; and the subsequent activation of natural killer (NK) cell interferon-yClFN-y) secretion and lytic activity. Animal studies suggest that CpG ODN may be therapeutically useful as vaccine adjuvants, antiallergens, chemotherapeutic, and immunoprotective agents.Although the immune effects of CpG-ODN have been widely studied, its biological activities are not comprehensively understood. To gain more knowledge of the biological activities of CpG-ODN, we had used DNA microarray to profile the gene expression in immune cell line after CpG-ODN treatment, and found that somegenes related to formation of macrophage foam cell upregulated. We reasoned that CpG-ODN might impact lipid metabolism and formation of foam cell. Foam cells are characteristic pathological cells in the lesions of atherosclerosis. Excess lipid loading in macrophage results in the formation of foam cell. It is a key process in the early stages of the atherosclerotic lesion. So it is very important to elucidate the fact that CpG-ODN might affect the formation of foam cells.In the study presented herein,we investigated the immune cells treated by CpG-ODN using cDNA microarray technology, and found those upregulated or downregulated genes related to cell cycle, immune modulation and signal transduction. Surprisingly, we also found the expression of 3 genes, which are CDS 6 (NM₀07643X LPL (NM₀08509) and Fcy2b (NM₀10187) ,increased markedly. The results were further confirmed by semiquantitative RT-PCR. Furthermore, we demonstrated that CpG-ODN could affect the formation of foam cells by histochemical and HPLC analysis. CD36, LPL and Fcy2b were thought closely related to lipid metabolism and formation of macrophage foam cell. So CpG-ODN could modulate the gene expression of foam cell, and affect the process of atherosclerosis.Macrophage-derived foam cells in atherosclerotic lesions are generally thought to play a major role in the pathology of the disease. The uptake of oxidized low density lipoprotein (ox-LDL) by macrophages is a key event implicated in the initiation and development of atherosclerotic lesions. Two macrophage surface receptors, CD36 (a class B scavenger receptor) and the macrophage scavenger receptor (a class A scavenger receptor), have been identified as the major receptors that bind and internalize oxidized low density lipoprotein (ox-LDL). CD36 is an 88-Kda transmembrane glycoprotein expressed on monocytes, platelets, and micro vascular endothelium. Expression of CD36 in monocyte/macrophages in tissue culture is dependent both on the differentiation state as well as exposure to solu...