Involvement of CD14 in the inhibitory effects of dimethyl-alpha-cyclodextrin on lipopolysaccharide signaling in macrophages.
The potential use of alpha-cyclodextrin and its hydrophilic alpha-cyclodextrin derivatives (alpha-CyDs) as antagonists against lipopolysaccharide (LPS), which stimulates the nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) production as well as nuclear factor-kappaB (NF-kappaB) activation in macrophages was examined. Of three alpha-CyDs used in the present study, 2,6-di-O-methyl-alpha-CyD (DM-alpha-CyD) had greater inhibitory activity than did the other CyDs against NO and TNF-alpha 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-alpha-CyD inhibited NF-kappaB translocation into nucleus. These inhibitory effects of DM-alpha-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-alpha-CyD may have promise as a potent and unique antagonist for excess activation of macrophages stimulated with LPS.
Motoyama
Keiichi
K
Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1, Oe-honmachi, Kumamoto 862-0973, Japan.
Arima
Hidetoshi
H
Nishimoto
Yoji
Y
Miyake
Kensuke
K
Hirayama
Fumitoshi
F
Uekama
Kaneto
K
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry; D015536:Down-Regulation; D015870:Gene Expression / Q000187:drug effects; D018950:Lipopolysaccharide Receptors / Q000502:physiology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000276:immunology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000032:analysis / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010743:Phospholipids / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D047391:alpha-Cyclodextrins / Q000494:pharmacology*
D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010743:Phospholipids; D014409:Tumor Necrosis Factor-alpha; D047391:alpha-Cyclodextrins; C479660:dimethyl-alpha-cyclodextrin; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse