Sensitization of human neutrophil defense activities through activation of platelet-activating factor receptors by ginkgolide B, a bioactive component of the Ginkgo biloba extract EGB 761.
Ginkgolide B (GKB, BN 52021) was described as a platelet-activating factor (Paf) receptor antagonist. However, it is not known whether all GKB biological effects are mediated through Paf receptor antagonism only. To gain insight into the drug mode of action, we investigated here the effects of GKB per se on functional and signaling activities in human polymorphonuclear leukocytes (PMN). Treatment of PMN with GKB (0.5-12 microM) stimulates a rapid and weak production of reactive oxygen species determined by chemiluminescence. ROS production required the activation of protein kinase C (PKC), tyrosine kinases and p38 mitogen-activated protein kinase as indicated by inhibitory effects of, respectively, GF 109203X (IC(50) of 0.5 microM), genistein (IC(50) of 0.5 microM) and SB 203580 (IC(50) of 0.2 microM) or SB 202190 (IC(50) of 1.1 microM). GKB stimulated a Pertussis toxin-sensitive PLD activity assessed by the formation of tritiated phosphatidic acid and choline. By contrast, GKB did prevent the Paf-mediated PLD activity and CL response (IC(50) of 2 microM). Interestingly, both GKB and Paf-induced CL response were prevented by selective Paf antagonists such as CV 6209 or WEB 2086 indicating that GKB may directly activate Paf receptors. Finally, GKB potentiated the CL response induced by fMet-Leu-Phe and zymosan. These results show that GKB is the first partial agonist of the Paf receptor described so far capable of priming the polymorphonuclear leukocyte function.
Lenoir
Monique
M
CNRS UPRES-A 8068, Département de Biologie Cellulaire, ICGM, Hôpital Cochin, 27 rue du Faubourg St. Jacques, 75679 Paris Cedex 14, France.
Pedruzzi
Eric
E
Rais
Samira
S
Drieu
Katy
K
Perianin
Axel
A
D001381:Azepines / Q000494:pharmacology; D002352:Carrier Proteins / Q000494:pharmacology; D004224:Diterpenes; D015536:Down-Regulation; D004789:Enzyme Activation; D005343:Fibrinolytic Agents / Q000494:pharmacology; D020441:Ginkgo biloba / Q000737:chemistry*; D046934:Ginkgolides; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D007783:Lactones / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D037342:Pertussis Toxin; D010739:Phospholipase D / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011726:Pyridinium Compounds / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D016897:Respiratory Burst / Q000187:drug effects*; D014230:Triazoles / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D001381:Azepines; D002352:Carrier Proteins; D004224:Diterpenes; D005343:Fibrinolytic Agents; D046934:Ginkgolides; D047908:Intracellular Signaling Peptides and Proteins; D007783:Lactones; D010936:Plant Extracts; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D011726:Pyridinium Compounds; D017382:Reactive Oxygen Species; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D014230:Triazoles; D010566:Virulence Factors, Bordetella; C039351:platelet activating factor receptor; C015482:protein kinase modulator; C053321:CV 6209; C052518:WEB 2086; C045856:ginkgolide B; D037342:Pertussis Toxin; D010739:Phospholipase D