Kim Bo-Young, Son Yonghae, Lee Jeonga, Choi Jeongyoon, Kim Chi Dae, Bae Sun Sik, Eo Seong-Kug, Kim Koanhoi
Department of Pharmacology, Pusan National University-School of Medicine, Yangsan, Gyeongnam, Republic of Korea.
College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan, Jeonbuk, Republic of Korea.
PLoS One. 2017 Dec 13;12(12):e0189643. doi: 10.1371/journal.pone.0189643. eCollection 2017.
Molecular mechanisms underlying the decreased number of macrophages and T cells in the arteries of cholesterol-fed-rabbits following dexamethasone administration are unknown. We investigated the possibility that dexamethasone could affect activation of monocytic cells induced by oxygenated derivatives of cholesterol (oxysterols) using THP-1 monocyte/macrophage cells. 27-Hydroxycholesterol (27OHChol), an oxysterol elevated with hypercholesterolemia, enhanced production of CCL2, known as MCP1, chemokine from monocytes/macrophages and migration of the monocytic cells, but the CCL2 production and the cell migration were reduced by treatment with dexamethasone. Dexamethasone inhibited superproduction of CCL2 induced by 27OHChol plus LPS and attenuated transcription of matrix metalloproteinase 9 as well as secretion of its active gene product induced by 27OHChol. The drug downregulated cellular and surface levels of CD14 and blocked release of soluble CD14 without altering transcription of the gene. Dexamethasone also inhibited expression and phosphorylation of the NF-κB p65 subunit enhanced by 27OHChol. Collectively, these results indicate that dexamethasone inhibits activation of monocytes/macrophages in response to 27OHChol, thereby leading to decreased migration of inflammatory cells in milieu rich in oxygenated derivatives of cholesterol.
给予地塞米松后，胆固醇喂养的兔子动脉中巨噬细胞和T细胞数量减少的分子机制尚不清楚。我们使用THP-1单核细胞/巨噬细胞研究了地塞米松是否会影响胆固醇氧化衍生物（氧化甾醇）诱导的单核细胞激活的可能性。27-羟基胆固醇（27OHChol）是一种在高胆固醇血症时升高的氧化甾醇，可增强单核细胞/巨噬细胞中CCL2（即MCP1趋化因子）的产生以及单核细胞的迁移，但地塞米松处理可降低CCL2的产生和细胞迁移。地塞米松抑制27OHChol加LPS诱导的CCL2过量产生，并减弱基质金属蛋白酶9的转录以及27OHChol诱导的其活性基因产物的分泌。该药物下调细胞和表面CD14水平，并阻断可溶性CD14的释放，而不改变基因转录。地塞米松还抑制27OHChol增强的NF-κB p65亚基的表达和磷酸化。总体而言，这些结果表明地塞米松抑制单核细胞/巨噬细胞对27OHChol的激活，从而导致富含胆固醇氧化衍生物环境中炎症细胞迁移减少。
