Differential regulation of human eosinophil, macrophage, and neutrophil functions by the allergic mediator release inhibitor CI-959.
The cell activation inhibitor CI-959 [5-methoxy-3-(1-methyl-ethoxy)-N-1H- tetrazol-5-ylbenzo[b]thiophene-2-carboxamide, monosodium salt] was evaluated for its effect on the activation of human eosinophils, macrophages, and neutrophils by the phagocytic stimulus serum-opsonized zymosan (SOZ). CI-959 inhibited the respiratory burst of eosinophils and neutrophils, measured as the generation of superoxide anion, with IC50s of 9.6 and 14.5 microM, respectively. In contrast, 100 microM CI-959 inhibited superoxide anion generation by human macrophages by only 22.7%. The compound exhibited a different inhibition profile for lysosomal enzyme release from these cells. At 100 microM, CI-959 inhibited the release of eosinophil peroxidase and macrophage N-acetyl-beta-D-glucosaminidase by only 19.5 and 25.6%, respectively. In contrast, CI-959 inhibited the release of the neutrophil primary granule enzyme myeloperoxidase with an IC50 of 7.5 microM, while inhibiting release of lysozyme from secondary granules by only 11.4% at 100 microM. These results demonstrate that oxygen radical generation and lysosomal enzyme release by human leukocyte populations are differentially regulated by CI-959.
Wright
C D
CD
Immunopathology Department, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
Devall
L J
LJ
Aker
K A
KA
Thueson
D O
DO
Conroy
M C
MC
D015536:Down-Regulation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004804:Eosinophils / Q000187:drug effects* / Q000201:enzymology; D005609:Free Radicals; D006801:Humans; D066298:In Vitro Techniques; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology; D010101:Oxygen Consumption / Q000187:drug effects; D016897:Respiratory Burst / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D005609:Free Radicals; D013777:Tetrazoles; D013876:Thiophenes; D013481:Superoxides; C061662:CI 959