Stimulation of neutrophil oxidative metabolism by indomethacin

Human neutrophils exposed to indomethacin demonstrate an enhanced capacity for superoxide ion (O2-) generation when stimulated with opsonized zymosan. Enhancement is not seen with indomethacin-treated cells exposed to soluble oxidative stimuli. To further investigate this phenomenon, O2- generation, chemiluminescence, and phagocytosis were assessed in human neutrophils preincubated with indomethacin. Zymosan-stimulated O2- release was increased from 150 to 300% of controls in neutrophils exposed to 400 micrograms/ml indomethacin. Enhancement was not reversed by removal of indomethacin from the medium prior to addition of the stimulus and was dose-dependent at drug concentrations of 5 to 400 micrograms/ml. Neutrophils exposed to methacin alone also generated more O2- than control cells, although this increment was not sufficient to account for the degree of enhancement seen when indomethacin-treated cells were exposed to zymosan. Neutrophil chemiluminescence induced by zymosan was also increased by exposure to indomethacin, and at a drug concentration of 400 micrograms/ml (1.1 mM) enhancement ranged from 253 to 333% of controls. As was observed with O2- generation, chemiluminescence of neutrophils was increased in the presence of indomethacin alone, although, to a degree far less than was seen when drug-treated cells were stimulated with zymosan. Phagocytosis of radiolabeled S. aureus by neutrophils incubated with indomethacin was increased 13 +/- 5% over controls (P less than 0.01, n = 5), but was unaltered by incubation of cells with the buffer used to solubilize the drug. The modest degree of enhancement of phagocytosis suggests that increased particle uptake is not the sole mechanism of oxidative enhancement.(ABSTRACT TRUNCATED AT 250 WORDS)