동맥경화 진행과정의 Monocyte chemotactic protein-3 신호전달에 관한 연구
Studies on MCP-3 signaling on the process of atherogenesis
ii, 81 p.
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Human monocyte chemotactic protein-3 (MCP-3) belongs to CC chemokines, which are cytokines involved in the cell recruitment, inflammation and carcinogenesis. Especially, the expressional level of MCP-3 gene is increased by oxidized low-density lipoproteins (oxLDL), suggesting that it might have a strong relationship with atherosclerosis. The oxLDL has been shown to induce peroxisome proliferator activated receptorγ (PPARγ), one of the nuclear receptors, which aslo shown to function as a transcriptional factor involved in the adipocyte differentiation and the entire lipid metabolism. The PPARγ regulates gene expression in response to various activator, including 15-deoxy-Δ12,14-prostaglandin J2(15d-PGJ2) and thiazolidinedione (TZD) which are agonists of the PPARγ. The PPARγ binds preferentially to PPAR response element (PPRE) through cooperative interactions by forming a heterodimer with corresponding partner, retinoid X receptor (RXR), in order to regulate transcription. The RXR is a receptor for the 9-cis-retinoic acid, one of metabolites of vitamin A. It plays a central role in the regulation of intracellular receptor signalling and mediate ligand-dependent transcription. Recently, it was reported that PPARγ:RXR heterodimer can regulate the gene expression and differentiation of the monocyte and is expressed at a high level in the foam cells of atherosclerotic lesions. It has been suggested that MCP-3 gene expression has a deep connection with PPARγ:RXR heterodimer. In this study, we investigated the effects of the endogenous PPARγ ligand(15d-PGJ2) and RXR specific ligand (9-cis-retinoic acid) in human monocytic THP-1 cells using Northern blots, immunocytochemistry and microarray. The expression of PPARγ gene, induced by the addition of 15d-PGJ2 and 9-cis-retinoic acid in the culture media, also induced MCP-3 gene expression. The level of MCP-3 gene expression was shown to be especially high in a specific-concentration of the 15d-PGJ2 in combination with 9-cis-retinoic acid. In this concentration, it was found that the PEA-3 gene is expressed in the same pattern with that of MCP-3. It has previously shown that there is a PEA-3 binding element on the promotor of MCP-3 gene. The PEA-3 appears to bind with PEA-3 binding element on the MCP-3 promoter and seems to be involved in transcriptional regulation of the human MCP-3 gene. On the other hand, it was found in this study that the more MCP-3 gene expressed, the less expressed LXR gene, suggesting an opposite role between RXR and LXR in the aspect of atherogenesis. In the microarray analyses using an entire expressed genes in the THP-1 cells after addition of MCP-3 protein into the culture media, numerous genes were found to be differentially expressed, which are related to atherogenesis, differentiation, apoptosis, inflammation and others. Those genes are needed to be investigated further. In conclusion, the signal from the oxLDL seems to be transmitted to the MCP-3 via PPARγ:RXR (or LXR) heterodimer followed by the binding of PEA-3 on the promotor site of MCP-3 gene, which might be important in the entire mechanism of atherogenesis.