| 摘要: | 肝臟X受器(liver X receptor)為脂類代謝和發炎反應的重要調節因子。先前我們實驗室的研究發現，三種肝臟X受器促效劑例如T0901317、GW3965和ATI-111在人類U937單核細胞和巨噬細胞中對於肝臟X受器和其他相關基因像是CD11、RXRα、SREBP-1c、resistin、MCP-1和CCL5的表現量有不同的影響。本篇研究擬進一步探討這三個肝臟X受器促效劑在佛波醇12- 肉荳蔻酸酯13- 乙酸酯(phorbol 12-myristate 13-acetate)分化劑誘導人類U937單核細胞到巨噬細胞為期四天的分化過程中是否會影響肝臟X受器和上述相關基因的表現量。結果顯示，在分化過程中，CD11a、CD11b、CD11c、LXRβ、RXRα、MCP-1與CCL5等基因的表現量皆增加，但LXRα、SREBP-1c與resistin mRNA表現量卻降低。單獨處理肝臟X受器促效劑二天與四天後，T0901317、GW3965和ATI-111三種藥物皆促進LXRα與SREBP-1c的基因表現，降低了MCP-1 mRNA表現量，卻沒有改變CD11、LXRβ、RXRα、resistin和CCL5的基因表現。然而，在有PMA處理細胞的情況下，我們發現肝臟X受器促效劑T0901317在U937單核細胞分化過程中，更增加了CD11b、LXRβ與CCL5基因表現量，更降低了resistin基因表現，不過，T0901317防止了PMA所誘導增加MCP-1基因表現的作用和PMA所誘導減少LXRα和SREBP-1c基因表現的作用，並沒有改變PMA所誘導增加CD11a、CD11c與RXRα的表現量之作用。另一方面，另兩種肝臟X受器促效劑例如GW3965和ATI-111有類似的作用，不同的是GW3965更增加了PMA所誘導CD11a與CD11c基因表現量之增加作用，ATI-111卻更增加了PMA所誘導CD11c基因表現量之增加作用。以上結果說明了這三個肝臟X受器促效劑在U937單核細胞分化成巨噬細胞的期間中對於基因的影響，會隨著基因種類而異，並與分化的過程有關。本研究成果針對肝臟X受器促效劑對於U937單核細胞分化成巨噬細胞、脂質代謝與炎症的作用，可協助釐清以上三型肝臟X受器促效劑的差異性作用。;Liver X receptors are important modulators of lipid metabolism and inflammatory response. Previously our laboratory had found that the three LXR agonists, such as T0901317, GW3965 and ATI-111, acted slightly differently on the expression of LXR and other related genes, such as CD11, RXRα, SREBP-1c, resistin, MCP-1, and CCL5 in human U937 monocyte and macrophage. We herein studied whether all three LXR agonists differentially affected mRNA expression of LXR and the above genes during the 4-day period of U937 monocyte differentiation to macrophage induced by phorbol 12-myristate 13-acetate (PMA). First, CD11a, b, and c, LXRβ, RXRα, MCP-1, and CCL5 genes expressed higher during the differentiation, while LXRα, SREBP-1c and resistin gene expression declined. Second, T0901317, GW3965, and ATI-111 alone stimulated the expression of LXRα, SREBP-1c mRNAs, and decreased levels of MCP-1 mRNA, and unaltered levels of CD11, LXRβ, RXRα, resistin, and CCL5 mRNAs after 2 and 4 days of treatment. In the presence of PMA, T0901317 enhanced the PMA-increased levels of CD11b, LXRβ, and CCL5 mRNAs and the PMA-decreased levels of resistin mRNA. However, it blocked the PMA-decreased levels of LXRα and SREBP-1c mRNAs and the PMA-increased levels of MCP-1 mRNA, and unaltered PMA-increased levels of CD11a, CD11c, and RXRα mRNAs. Similar effects of GW3965 and ATI-111 to T0901317 on the PMA-altered levels of LXRα, LXRβ, RXRα, SREBP-1c, resistin, MCP-1 and CCL5 mRNAs were observed, except that GW3965 enhanced the PMA-increased expression of CD11a and CD11c mRNAs and that ATI-111 enhanced the PMA-increased expression of CD11c mRNA. These data suggest that the effect of LXR agonist on gene expression during the differentiation of monocytes into macrophages varies with the types of genes and associates with the process of differentiation. Results of the study may help clarify the different magnitudes of actions of different LXR agonists on differentiation of U937 monocytes into macrophages, lipid metabolism and inflammation. |
