Prevention of macrophage adhesion molecule-1 (Mac-1)-dependent neutrophil firm adhesion by taxifolin through impairment of protein kinase-dependent NADPH oxidase activation and antagonism of G protein-mediated calcium influx.
Taxifolin has been reported to down-regulate the expression of intercellular adhesion molecule-1 (ICAM-1), a receptor-mediating firm adhesion with beta2 integrin (e.g., Mac-1) expressed on leukocytes. To evaluate whether taxifolin could modulate Mac-1-dependent firm adhesion by neutrophils, and the possible mechanism(s) underlying its anti-inflammatory action, its effects on N-formyl-methionyl-leucyl-phenylalanine (fMLP) or phorbol-12-myristate-13-acetate (PMA)-activated peripheral human neutrophils were studied. Pretreatment with taxifolin (1-100 microM) concentration-dependently diminished fMLP- or (PMA)-induced Mac-1-dependent firm adhesion and upexpression of surface Mac-1. Mobilisation of intracellular calcium and production of reactive oxygen species (ROS) signal the upexpression of Mac-1 and firm adhesion by neutrophils. Taxifolin impeded the calcium influx induced by fMLP (a receptor-mediated activator) or AlF(4)(-) (a G protein-mediated activator). Taxifolin also effectively inhibited the fMLP- or PMA-induced ROS production with 50% inhibitory concentration (IC(50)) less than 10microM, possibly through impairing the activation of NADPH oxidase, a major ROS-generating enzyme in neutrophils, by restricting the activation of p38 mitogen-activated protein kinase (p38 MAPK) and protein kinase C (PKC). In conclusion, we propose that impairment of ROS production by NADPH oxidase through interfering with p38 MAPK- and/or PKC-dependent signals, and antagonism of G protein-mediated calcium influx may account for the inhibition of Mac-1-dependent neutrophil firm adhesion that confers taxifolin the anti-inflammatory activity.
Wang
Yea-Hwey
YH
Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
Wang
Wen-Yen
WY
Liao
Jyh-Fei
JF
Chen
Chieh-Fu
CF
Hou
Yu-Chang
YC
Liou
Kuo-Tong
KT
Chou
Yueh-Ching
YC
Tien
Jung-Hsiung
JH
Shen
Yuh-Chiang
YC
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D044948:Flavonols / Q000494:pharmacology*; D005609:Free Radicals / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D016177:Macrophage-1 Antigen / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases; D019255:NADPH Oxidases / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects*; D011493:Protein Kinase C / Q000378:metabolism; D011794:Quercetin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation; D014969:Xanthine Oxidase / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015815:Cell Adhesion Molecules; D044948:Flavonols; D005609:Free Radicals; D016177:Macrophage-1 Antigen; D017382:Reactive Oxygen Species; D011794:Quercetin; C003377:taxifolin; D014969:Xanthine Oxidase; D019255:NADPH Oxidases; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins; D002118:Calcium