Induction of nitric oxide synthase activity in phagocytic cells inhibited by tricyclodecan-9-yl-xanthogenate (D609).
1. The synthesis of nitric oxide (NO) by immune-stimulated murine phagocytic cells (J774) and the modulation of this synthesis by tricyclodecan-9-yl-xanthogenate (D609), a specific inhibitor of phosphatidylcholine-specific phospholipase C (PC-PLC), was investigated. D609 dose-dependently suppressed production of NO, as measured by the release of nitrite and nitrate, in response to lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) in intact cultured cells with an IC50 of approximately 20 micrograms ml-1. D609 at 40 micrograms ml-1 completely abrogated immune-stimulated nitrite production. 2. The inhibitory effects of D609 on nitrite production were time-dependent and restricted to the first 18 h post-stimulation. D609 did not inhibit nitrite production in the cytosol of immune-stimulated phagocytes. 3. These findings indicate that the xanthogenate, D609, is a potent inhibitor of the induction of NO-synthase activity in immune-stimulated phagocytes. Furthermore, since D609 has been demonstrated to inhibit PC-PLC specifically, our findings suggest that the activation of this enzyme by LPS and IFN-gamma is a proximal step in the signal transduction of inducible NO-synthase in phagocytic cells.
Tschaikowsky
K
K
Institute of Anesthesiology, University of Erlangen-Nuremberg, Germany.
Meisner
M
M
Schönhuber
F
F
Rügheimer
E
E
D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis*; D000818:Animals; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D002478:Cells, Cultured; D004075:Diglycerides / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology*; D051379:Mice; D019001:Nitric Oxide Synthase; D009636:Norbornanes; D011493:Protein Kinase C / Q000502:physiology; D015398:Signal Transduction; D013859:Thiocarbamates; D013871:Thiones / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors* / Q000502:physiology
D001952:Bridged-Ring Compounds; D004075:Diglycerides; D008070:Lipopolysaccharides; D009636:Norbornanes; D013859:Thiocarbamates; D013871:Thiones; C046498:tricyclodecane-9-yl-xanthogenate; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D011493:Protein Kinase C; D010738:Type C Phospholipases