Abstract
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.
Footnotes
- Received May 21, 1998.
- Accepted September 24, 1998.
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Send reprint requests to: Dr. Yen-Jen Sung, Institute of Anatomy and Cell Biology, School of Life Science, National Yang-Ming University, 155 Li-Nung St., Section 2, Shih-Pai, Taipei, Taiwan. E-mail: yjsung{at}mailsrv.ym.edu.tw
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This study was supported, in part, by Grants NSC87 to 2314-B-010-082, NSC88 to 2314-B-010-098-M49 (to Y.J.S.), NSC87-2314-B-077-015, and NSC88-2314-B-077-011 (to C.F.C.) from the National Science Council and NRICM-87106 (to Y.J.S.) from the National Research Institute of Chinese Medicine, Taiwan, Republic of China.
- The American Society for Pharmacology and Experimental Therapeutics
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