Differential regulation of the activation of human eosinophils, macrophages, and neutrophils: effect of the allergic mediator release inhibitor CI-949.
The allergic mediator release inhibitor CI-949 [5-methoxy-3-(1- methylethoxy)-1-phenyl-N-1H-tetrazol-5-yl-1H-indole-2-carbox amide L-arginine salt] was evaluated for its effect on the activation of human eosinophils, macrophages, and neutrophils by the phagocytic stimulus serum-opsonized zymosan (SOZ). CI-949 inhibited the SOZ- stimulated respiratory burst of eosinophils, measured as the generation of superoxide anion, with an IC50 of 22.8 microM. At concentrations of 100 microM, CI-949 had no inhibitory effect against lysosomal enzyme release by these cells. At 100 microM, CI-949 had no inhibitory effect against release of eosinophil peroxidase while inhibiting release of the macrophage lysosomal enzyme N-acetyl-beta-D- glucosaminidase by only 11.7 percent. In contrast, CI-949 inhibited the release of the neutrophil primary granule enzyme myeloperoxidase inhibiting of 21.4 microM, while inhibiting release of lysozyme from lysosomal enzyme release from secondary granules with an IC50 of 99.3 microM. These results demonstrate that oxygen radical generation and lysosomal enzyme release by human eosinophils, macrophages and neutrophils are differentially regulated by CI-949. These results suggest that these inflammatory cells may have distinct stimulus-related coupling mechanisms.
Wright
C D
CD
Experimental Therapy Department, Warner-Lamber Company, Ann Arbor, MI 48104
Devall
L J
LJ
Aker
D O
DO
Thueson
D O
DO
Conroy
M C
MC
D000118:Acetylglucosaminidase / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004804:Eosinophils / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008247:Lysosomes / Q000201:enzymology; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects*; D009195:Peroxidase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D015054:Zymosan / Q000494:pharmacology
D004791:Enzyme Inhibitors; D013777:Tetrazoles; D013876:Thiophenes; D013481:Superoxides; C061662:CI 959; D015054:Zymosan; D009195:Peroxidase; D000118:Acetylglucosaminidase