High density lipoprotein (HDL) receptor, scavenger receptor class B, type I (SR-BI), mediates selective cholesteryl ester uptake from lipoproteins into the liver as well as cholesterol efflux from macrophages to HDL. Recently, strong evidence has demonstrated the anti-inflammatory effect of HDL, although the mechanism of action is not fully understood. In this study, we showed that the anti-inflammatory effects of HDL are dependent on SR-BI expression in THP-1 macrophages. Consistent with earlier findings, pretreatment of macrophages with HDL abolished LPS-induced TNF alpha production. HDL also inhibited LPS-induced NF-kappa B activation. In addition, knockdown of SR-BI or inhibition of SR-BI ligand binding abolished the antiinflammatory effect of HDL. SR-BI is a multi-ligand receptor that binds to modified lipoproteins as well as native HDL. Since modified lipoproteins have pro-inflammatory properties, it is unclear whether SR-BI activated by modified HDL has an anti- or pro-inflammatory effect. Glycated HDL induced NF-kappa B activation and cytokine production in macrophages in vitro, suggesting a pro-inflammatory effect for modified HDL. Moreover, inhibition of SR-BI function or expression potentiated glycated HDL-induced TNF-alpha production, suggesting an anti-inflammatory effect for SR-BI. In conclusion, SR-BI plays an important function in regulating HDL-mediated anti-inflammatory response in macrophages. (C) 2014 Elsevier Inc. All rights reserved.