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:MβCD in the presence or absence of ezetimibe. We found that ezetimibe dramatically down-regulated the expression of the tumor necrosis factor-α (TNF-α) gene. Consistent with the microarray results, TNF-α protein levels were inhibited by ezetimibe. Moreover, ezetimibe suppressed the promoter activity of TNF-α but not TNF-α lacking the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) binding domain in THP-1 cells treated with phorbol myristate acetate and Chol:MβCD. Furthermore, treatment of THP-1 macrophages with ezetimibe resulted in the degradation of IκB and subsequently inhibited nuclear translocation of NF-κB 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-κB. Collectively, our results demonstrated that the anti-inflammatory properties of ezetimibe in THP-1 macrophages are, at least in part, through suppression of NF-κB activation via the MAPK pathway. These data provide direct evidence for the potential application of ezetimibe in the prevention and treatment of inflammatory diseases.