RT Journal Article
SR Electronic
T1 Impediment to Calcium Influx and Reactive Oxygen Production Accounts for the Inhibition of Neutrophil Mac-1 Up-Regulation and Adhesion by Tetrandrine
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 186
OP 193
DO 10.1124/mol.55.1.186
VO 55
IS 1
A1 Yuh-Chiang Shen
A1 Chieh-Fu Chen
A1 Sheng-Yuan Wang
A1 Yen-Jen Sung
YR 1999
UL http://molpharm.aspetjournals.org/content/55/1/186.abstract
AB We studied the mechanisms by which the plant alkaloid tetrandrine (TTD) inhibits Mac-1-dependent neutrophil adhesion to fibrinogen. TTD (0.1–10 μM) significantly inhibited Mac-1 up-regulation and neutrophil adhesion, as induced byN-formyl-methionyl-leucyl-phenylalanine (fMLP) or phorbol-myristate-acetate (PMA). Treatment of neutrophils with fMLP or PMA caused a rapid influx of Ca++ and accumulation of reactive oxygen species (ROS), both of which have been shown to enhance neutrophil adhesion via Mac-1 up-regulation. Because TTD antagonizes Ca++ influx and abrogates ROS, we examined the relationship between Ca++ influx, ROS formation, and Mac-1 expression in TTD-inhibited neutrophil adhesion. TTD alone caused a slight but statistically significant increase in [Ca++]iwith no effect on adhesion. In contrast, TTD as well as two Ca++ channel antagonists, verapamil and nifedipine, markedly diminished fMLP- and PMA-induced Ca++ influx, Mac-1 up-regulation, and adhesion. TTD also inhibited increases in [Ca++]i and adhesion induced by the ionophore A23187 but failed to inhibit those induced by thapsigargin, an agent mobilizing Ca++ from intracellular stores. Thus, TTD impeded Ca++ influx from outward to avert neutrophil adhesion. Similarly, TTD and two ROS scavengers, superoxide dismutase and catalase, abolished ROS production, Mac-1 up-regulation, and neutrophil adhesion. Ca++ and ROS, therefore, represent two essential signals for Mac-1 up-regulation upon fMLP or PMA stimulation. Our data suggest that the antiadherent effect of TTD is mediated, in part, by the inhibition of Ca++ influx and ROS formation, resulting in suppressed up-regulation of Mac-1 and, in turn, neutrophil adhesion to fibrinogen.