Inhibition of human neutrophil activation by the allergic mediator release inhibitor, CI-922: differential inhibition of responses to a variety of stimuli.
The allergic mediator release inhibitor 3,7-dimethoxy-4-phenyl-N-1H-tetrazol-5-yl-4H-furo[3,2-b]indole-2- carboxamide, L-arginate (CI-922) is a potent inhibitor of human neutrophil functions in vitro. Over a concentration range from 1 to 100 mumol CI-922 inhibits the chemotactic response of neutrophils to the synthetic chemotaxin N-formyl-methionyl-leucyl-phenylalanine (FMLP). CI-922 also inhibits respiratory and secretory responses of neutrophils in response to agents that stimulate phospholipase C-dependent phosphoinositide hydrolysis to generate the second messengers inositol 1,4,5, trisphosphate and 1,2 diacylglycerol, including: the plasma membrane receptor-specific ligands FMLP and C5a; serum-opsonized zymosan; concanavalin A; and the guanine nucleotide regulatory protein-specific stimulus guanosine-5'-0-(3-thiotriphosphate) (GTP gamma S). CI-922 also inhibits neutrophil functions stimulated by the calcium ionophore A23187. In contrast, CI-922 does not inhibit neutrophil responses to protein kinase C-specific stimuli such as phorbol 12-myristate 13-acetate (PMA) or L-alpha-1,2 dioctanoylglycerol (DiC8). CI-922 also fails to inhibit the synergistic activation of the respiratory burst by suboptimal concentrations of PMA and calcium ionophore A23187. The observation that CI-922 inhibits neutrophil responses to a variety of soluble and particulate stimuli, excluding protein kinase C-specific stimuli, allows us to postulate the site of action of the compound. We propose that CI-922 inhibits neutrophil activation at a site distal to signal transduction through the guanine nucleotide regulatory protein required for second messenger generation but proximal to phosphorylation reactions mediated by protein kinase C and calmodulin-dependent protein kinases.
D001393:Azoles / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D007700:Kinetics; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology; D009113:Muramidase / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*
D001393:Azoles; D007211:Indoles; D010716:Phosphatidylinositols; D013777:Tetrazoles; D013481:Superoxides; D009240:N-Formylmethionine Leucyl-Phenylalanine; C045584:CI 922; D006861:Hydrogen Peroxide; D009195:Peroxidase; D009113:Muramidase