Mechanism of inhibition of human neutrophil activation by the allergic mediator release inhibitor, CI-922
The allergic mediator release inhibitor CI-922 (3,7-dimethoxy-4-phenyl-N-1H-tetrazol-5-yl-4H-furo(3,2-b)indole-2-carboxamide) is a potent inhibitor of human neutrophil (PMN) respiratory and secretory responses in vitro. At concentrations from 1 to 100 micromolar, CI-922 inhibits activation of PMNs by agents which stimulate phospholipase C-dependent phosphoinositide hydrolysis to generate the second messengers inositol 1,4,5 trisphosphate and diacylglycerol, including: the plasma membrane receptor-specific ligands fMet-Leu-Phe and C5a; concanavalin A; and the guanine nucleotide regulatory protein-specific stimulus GTPgammaS. In contrast, CI-922 does not inhibit PMN responses to protein kinase C-specific stimuli such as phorbol myristate acetate (PMA) or sn-1,2-dioctanoyl-glycerol. CI-922 is also unable to inhibit the synergistic activation of PMNs by suboptimal concentrations of PMA and calcium ionophore A23187. These results suggest that CI-922 inhibits PMN activation at a site distal to signal transduction through the guanine nucleotide regulatory protein required for second messenger generation but proximal cophosphorylation reactions mediated by protein kinase C and calcium/calmodulin-dependent protein kinases.
- Research Organization:
- Warner-Lambert/Parke-Davis, Ann Arbor, MI
- OSTI ID:
- 7117938
- Report Number(s):
- CONF-8604222-
- Journal Information:
- Fed. Proc., Fed. Am. Soc. Exp. Biol.; (United States), Journal Name: Fed. Proc., Fed. Am. Soc. Exp. Biol.; (United States) Vol. 45:4; ISSN FEPRA
- Country of Publication:
- United States
- Language:
- English
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63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ANIMALS
BIOLOGICAL EFFECTS
BIOLOGICAL MATERIALS
BLOOD
BLOOD CELLS
BODY FLUIDS
CARCINOGENS
CHEMICAL REACTIONS
DECOMPOSITION
ENZYMES
ESTERS
HYDROLYSIS
INHIBITION
LEUKOCYTES
LIPIDS
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MAMMALS
MAN
MATERIALS
NEUTROPHILS
ORGANIC COMPOUNDS
ORGANIC PHOSPHORUS COMPOUNDS
PHORBOL ESTERS
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PHOSPHORUS-GROUP TRANSFERASES
PHOSPHOTRANSFERASES
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SOLVOLYSIS
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