Comparison of the effects of indomethacin, RHC80267 and R59022 on superoxide production by 1,oleoyl‐2,acetyl glycerol and A23187 in human neutrophils

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.

The effect of non‐steroidal anti‐inflammatory drugs on the accumulation and release of interleukin‐1‐like activity by peritoneal macrophages from the mouse

“…Second, an effect of NSAIDs independent of the inhibition of cyclo-oxygenase appears to be responsible for the potentiation of LPS-induced release of IL-1 from the cell. It has been shown that concentrations of indomethacin higher than those required to inhibit prostaglandin production potentiate the release of superoxide from stimulated human neutrophils (Dale & Penfield, 1987). There is evidence that the potentiation of superoxide production by indomethacin is related to the ability of the drug to inhibit diacylglycerol metabolism, leading to a potentiation of protein kinase C activation (Dale & Penfield, 1987;Twomey & Dale, 1992).…”

“…Indomethacin has been shown to potentiate T-lymphocyte proliferation in vitro (Lewis & Barret, 1986) and plasma extravasation (Raud et al, 1987). Both indomethacin and sodium meclofenamate potentiate superoxide production by human neutrophils (Dale & Penfield, 1987;Twomey et al, 1989). Interleukin-l release by macrophages has also been shown to be potentiated by NSAIDs (Oppenheim et al, 1980;Brandwein, 1986;Knudsen et al, 1986;Kunkel et al, 1986;Sandborg et al, 1986).…”

“…Although there is evidence that PGE2 inhibits IL-1 release from macrophages (Kunkel et al, 1986) and that this may explain the potentiation by NSAIDs of IL-1 release, the potentiating action of NSAIDs on superoxide generation by human neutrophils appears to be unrelated to the inhibition of PGE2 synthesis by these drugs (Dale & Penfield, 1987;Twomey & Dale, 1992). There also remains the controversy in the literature regarding the ability of NSAIDs to potentiate IL-1 production from macrophages.…”

“…In addition, the possibility that NSAIDs regulate IL-1 production by inhibiting the metabolism of diacylglycerol is investigated since this has previously been postulated as a proinflammatory activity of NSAIDs with respect to superoxide generation by neutrophils. (Dale & Penfield, 1987;Twomey & Dale, 1992).…”

The effect of inhibition of both diacylglycerol metabolism and phospholipase A2 activity on superoxide generation by human neutrophils

“…However the cocktail of inhibitors marginally decreased receptorstimulated 02 production. An interpretation of these results must take cognisance of the possibility that indomethacin, in addition to its known effects on cyclooxygenase and phospholipase AZ, may also be an inhibitor of DAG metabolism [35]. Taking this possibility into account (and with the caveat that the inhibitors used could have actions other than the ones specified), one explanation for the increased 0; generation seen when these agents were used with post-receptor stimuli is that, since they could have inhibited DAG metabolism and increased DAG levels, the resultant increased protein kinase C activation could have more than compensated for the elimination of the putative arachidonate pathway(s).…”