Immunoregulatory effects of the flavonol quercetin in vitro and in vivo.
OBJECTIVE
Atherosclerosis is known to be an inflammatory disease. Dendritic cells (DCs) are essential for the regulation of the immune system. Up to 10% of the cells in atherosclerotic plaques are DCs. The cardiovascular protective effects of flavonoids (tea, wine) may be mediated by anti-inflammatory mechanisms that affect DC regulation. We aimed to characterize the impact of the flavonol quercetin on DC activity and differentiation in vitro and in vivo.


METHODS
For the in vitro experiments, we used murine DCs and endothelial cells to study adhesion properties. For all other experiments (DC phagocytosis capacity, DC maturation, DC differentiation (BDCA-1/-2) and NF-kB-activation), human monocyte-derived DCs were used. The cells were incubated with quercetin (10 μmol/L) ± oxLDL (10 μg/mL) between 24 and 48 h. For in vivo experiments, eight healthy male volunteers took 500 mg of quercetin twice daily over 4 weeks, five healthy male volunteers served as control. Before and after intake, blood samples were collected. Peripheral blood leukocytes were isolated (analyses of DC differentiation), and plasma was immediately frozen.


RESULTS
Quercetin reduced DC adhesion (-42%; p < 0.05) and expression of CD11a (-21%; p < 0.05). OxLDL-induced DC differentiation was partially inhibited by quercetin (BDCA-1-29%; BDCA-2-33%; p < 0.05). These effects were achieved by compensation of oxLDL-induced up-regulation of NF-kB by quercetin. The 4-week treatment with quercetin resulted in relevant plasma levels (2.47 μmol/L) and reduced BDCA-2 + DCs in the peripheral blood by 42% (p < 0.05) as well as systemic levels of the NO-synthase inhibitor asymmetric dimethylarginine (-31%, p < 0.05).


CONCLUSIONS
In vitro, quercetin reduced DC adhesion and oxLDL-induced DC differentiation. In vivo, quercetin reduced circulating plasmacytoid DCs and systemic ADMA-levels. The immunoregulatory effects of quercetin may contribute to the anti-atherosclerotic potential of flavonols.
Nickel
Thomas
T
Medizinische Klinik und Poliklinik I, Campus Grosshadern, Ludwig-Maximilians and University of Munich, 81377, Munich, Germany. tsnickel@web.de
Hanssen
Henner
H
Sisic
Zeljka
Z
Pfeiler
Susanne
S
Summo
Claudia
C
Schmauss
Daniel
D
Hoster
Eva
E
Weis
Michael
M
D000328:Adult; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood; D002448:Cell Adhesion; D002454:Cell Differentiation; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D004705:Endocytosis; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology / Q000276:immunology; D016328:NF-kappa B / Q000187:drug effects; D011794:Quercetin / Q000097:blood* / Q000494:pharmacology*; D015854:Up-Regulation
D000893:Anti-Inflammatory Agents; D008077:Lipoproteins, LDL; D016328:NF-kappa B; C099252:oxidized low density lipoprotein; C018524:N,N-dimethylarginine; D001120:Arginine; D011794:Quercetin