Involvement of CD14 in the inhibitory effects of dimethyl-α-cyclodextrin on lipopolysaccharide signaling in macrophages

The potential use of α-cyclodextrin and its hydrophilic α-cyclodextrin derivatives (α-CyDs) as antagonists against lipopolysaccharide (LPS), which stimulates the nitric oxide (NO) and tumor necrosis factor-α (TNF-α) production as well as nuclear factor-κB (NF-κB) activation in macrophages was examined. Of three α-CyDs used in the present study, 2,6-di-O-methyl-α-CyD (DM-α-CyD) had greater inhibitory activity than did the other CyDs against NO and TNF-α production through an impairment of gene expression in macrophage cell lines and primary macrophages stimulated with LPS and lipid A in a concentration-dependent manner. Concomitantly, DM-α-CyD inhibited NF-κB translocation into nucleus. These inhibitory effects of DM-α-CyD could be attributed to the release of CD14 from lipid rafts caused by an efflux of phospholipids, but not cholesterol. These results suggest that DM-α-CyD may have promise as a potent and unique antagonist for excess activation of macrophages stimulated with LPS.