No abstract

Indomethacin (10−4 m) causes marked augmentation of O−2release from human neutrophils when these are stimulated by either 1,oleoyl‐2,acetylglycerol or the divalent cation ionophore, A23187, the concentration‐response curve for each agent being shifted to the left and the maximum response to each increased. The diacylglycerol kinase inhibitor, R59022 (10−5 m) has effects very similar to those of indomethacin on both the 1,oleoyl‐2,acetylglycerol‐induced and the A23187‐induced concentration‐response curves for O2‐ generation. The diacylglycerol lipase inhibitor, RHC80267 (10−5 m) on the other hand, has a similar effect to indomethacin on 1,oleoyl‐2,acetylglycerol‐induced O−2 generation but, unlike indomethacin, has no effect on A23187‐induced O−2 generation. Comparison of the effects of these three agents provides a clue to the locus of the action of indomethacin in increasing superoxide release, suggesting that it may act as a diacylglycerol kinase inhibitor. A component of diacylglycerol lipase inhibition may also be present. It is suggested that these results could have relevance for the use of indomethacin as an anti‐inflammatory agent in chronic rheumatoid diseases.

Concentrations of phorbol myristate acetate and the calcium ionophore, A23 187, which by themselves are minimally effective in stimulating superoxide generation in human neutrophils show marked mutual potentiation when given together. This supports the hypothesis that synergism between cytosolic calcium and protein kinase C is involved in the stimulus/activation coupling of the respiratory burst in the neutrophil. NeutrophilPhorbol ester

Indomethacin at a concentration ( 1O-4 M) which depressed the effect on O,-generation by fMet-Leu-Phe, markedly enhanced 0; generation by both I-oleoyl-2-acetylglycerol and the calcium ionophore. A23187. These results are explicable in terms of the hypothesis that synergism between cytosolic calcium and protein kinase C is involved in signal transduction for the respiratory burst in the human neutrophil. NeutrophilSuperoxide Phorbol ester Indomethacin Calcium

Superoxide release from human neutrophils was stimulated either by receptor activation (using fMet-LeuPhe) or by activating, independently, each of the two pathways considered to be involved in signal transduction -calcium mobilization (using the ionophore, A23 187) and protein kinase C activation (using phorbol myristate acetate or I-oleoyl-2-acetylglycerol).Prostaglandin E, (3 x 10ms M) decreased &let-Leu-Phe-stimmated superoxide release, had no effect on superoxide release stimulated by A23 187, or by phorbol myristate acetate, and markedly enhanced the superoxide release stimulated by I-oleoyl-2-acetylglycerol. Similar enhancement was obtained with prostaglandin E,. Neutrophil Phorbol ester Protein kinase C Prostaglandin E fMet-Leu-Phe Phosphatidylinositol