Abstract 239: RXR Agonists Inhibit PMA-induced Differentiation Of Monocytic THP-1 Cells Into Macrophages
It is widely recognized that macrophages are important for atherosclerosis progression. Macrophages origin from circulating monocytes and differentiate into macrophages after entering arterial intima. The mechanisms of monocytes differentiating into macrophages are critical to the understanding of atherosclerosis prevention. Retinoid X Receptors (RXRs) are ligand-inducible transcriptional activators, whose agonists have been found drastically reduce the development of atherosclerosis. So in this study, we investigated the effect of RXR agonists on PMA-induced human monocytic THP-1 cells differentiation in vitro. THP-1 cells were differentiated into macrophage-like phenotype by incubation with 40nM PMA for 48h. Cell morphology was observed by phase contrast microscope and macrophage surface markers were analyzed by FACS. The viability of adherent differentiated THP-1 cells was determined by MTT assay. Fluorescence-labeled latex beads were used to analyze phagocytic activity. Cytokines TNF-α, IL-12, IFN-γ and MMP-9 levels were determined by ELISA assay. PMA-treated THP-1 cells acquired distinct macrophage-like phenotype as previously reported. RXR agonist 9-cisRA(10−8-10−7)and SR11237(10−7-10−6)both significantly decreased PMA-induced cell adhesion in dose-dependent manners. And the macrophage-like morphological changes produced by PMA were also inhibited by the two RXR agonists after 48hrs treatment. Flow cytometric studies indicated that the upregulated cell surface markers CD11b and CD14 by PMA were decreased about 49% and 37% by 9-cisRA(10−7), 38% and 32% by SR11237. The increased phagocytic activity by PMA was also reduced about 36% by 9-cisRA (10−7)and 29% by SR11237(10−6). 9-cisRA and SR11237 significantly decreased the upregulated levels of TNF-α, IL-12, IFN-γ and MMP-9 in PMA-differentiated cells in dose-dependent manners. Our study suggested that one of the antiatherosclerosis mechanisms of RXRs activation might be mediated by inhibiting monocyte/macrophage differentiation.