Anti-Inflammatory Activity of Ezetimibe by Regulating NF-κB/MAPK Pathway in THP-1 Macrophages

Inflammation plays a crucial role in atherosclerosis. Monocytes/ macrophages are involved in the inflammatory process during atherogenesis. Here, we performed daily gavage of ezetimibe in apolipoprotein E-deficient mice fed with a high-fat diet and found that ezetimibe administration decreased the level of C-reactive protein significantly. To investigate the potential molecular mechanism, we employed microarray analysis on the cultured macrophages treated with Chol: M beta CD in the presence or absence of ezetimibe. We found that ezetimibe dramatically down-regulated the expression of the tumor necrosis factor-a (TNF-alpha) gene. Consistent with the microarray results, TNF-alpha protein levels were inhibited by ezetimibe. Moreover, ezetimibe suppressed the promoter activity of TNF-alpha but not TNF-alpha lacking the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) binding domain in THP-1 cells treated with phorbol myristate acetate and Chol: M beta CD. Furthermore, treatment of THP-1 macrophages with ezetimibe resulted in the degradation of l kappa B and subsequently inhibited nuclear translocation of NF-kappa B and its transcriptional activity. Inhibition of the mitogen-activated protein kinase (MAPK) pathway using PD98059 attenuated the reduction effect of ezetimibe on the expression of NF-kappa B. Collectively, our results demonstrated that the anti-inflammatory properties of ezetimibe in THP-1 macrophages are, at least in part, through suppression of NF-kappa B activation via the MAPK pathway. These data provide direct evidence for the potential application of ezetimibe in the prevention and treatment of inflammatory diseases. (C) 2014 S. Karger AG, Basel