期刊
BIOCHEMICAL PHARMACOLOGY
卷 67, 期 8, 页码 1531-1539出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2003.12.020
关键词
calcium; G protein-coupled receptors; hyperforin; Hypericum perforatum; reactive oxygen species; phospholipase C
We have recently identified hyperforin, a lipophilic constituent of the herb Hypericum perforatum (St. John's wort), as a dual inhibitor of the proinflammatory enzymes cyclooxygenase-1 and 5-lipoxygenase. The aim of the present study was to further elucidate antiinflammatory properties and respective targets of hyperforin. We found that hyperforin inhibited the generation of reactive oxygen species (ROS) as well as the release of leukocyte elastase (degranulation) in human isolated polymorphonuclear leukocytes (PMNL), challenged by the G protein-coupled receptor (GPCR) ligand N-formyl-methionyl-leucyl-phenylalanine (fMLP) with an IC50 approximate to 0.3 muM. When PMNL were stimulated with phorbol-12-myristate-13-acetate (PMA) or ionomycin, hyperforin (up to 10 muM) failed to inhibit ROS production and elastase release, respectively. Moreover, hyperforin blocked receptor-mediated Ca2+ mobilization (IC50 approximate to 0.4 and 4 muM, respectively) in PMNL and monocytic cells, and caused a rapid decline of the intracellular Ca2+ concentration in resting cells. In contrast, the Ca2+ influx induced by ionomycin or thapsigargin was not suppressed. Comparative studies with the specific phospholipase C inhibitor U-73122 and hyperforin revealed similarities between both compounds. Thus, U-73122 and hyperforin blocked fMLP- and PAF-induced Ca2+ mobilization, ROS formation, and elastase release, but failed to suppress these responses when cells were stimulated by PMA or ionomycin. Also, both compounds rapidly decreased basal Ca2+ levels in resting cells and led to a rapid decline of the Ca2+ elevations evoked by fMLP or PAF Our data suggest that hyperforin targets component(s) within G protein signaling cascades that regulate Ca2+ homeostasis, coupled to proinflammatory leukocyte functions. (C) 2004 Elsevier Inc. All rights reserved.
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