THE EFFECT OF NONSTEROIDAL ANTIINFLAMMATORY DRUGS ON THE ACCUMULATION AND RELEASE OF INTERLEUKIN-1-LIKE ACTIVITY BY PERITONEAL-MACROPHAGES FROM THE MOUSE

1 The non-steroidal anti-inflammatory drugs (NSAIDs) indomethacin, 10 and 100 mu M, piroxicam, 100 mu M, and sodium meclofenamate, 1 and 100 mu M, potentiated the lipopolysaccharide (LPS)-stimulated release of interleukin-1 (IL-1)-like activity from mouse peritoneal macrophages. Aspirin up to 100 mu M was without effect. The drugs did not themselves stimulate the release of IL-1-like activity at the concentrations used. 2 LPS, 1 mu g ml(-1), stimulated prostaglandin E(2) production by mouse peritoneal macrophages and this was totally inhibited by aspirin, 100 mu M, indomethacin, 1 mu M, piroxicam, 10 mu M and sodium meclofenamate, 0.1 mu M. 3 The potentiation of LPS-stimulated release of IL-1-like activity produced by indomethacin, 100 mu M, piroxicam, 100 mu M, or sodium meclofenamate, 10 mu M, was inhibited by prostaglandin E(2), (PGE(2)) 10 ng ml(-1). 4 Aspirin, 100 mu M, indomethacin, 100 nM to 10 mu M, piroxicam, 1 to 100 mu M, and sodium meclofenamate, 10 nM, all potentiated cell-associated IL-1-like activity in LPS-stimulated macrophages. The drugs had no effect on cell-associated IL-1-like activity by themselves. 5 Exogenous PGE(2), 2 to 30 ng ml(-1), inhibited the cell-accumulation of IL-1-like activity stimulated by LPS in the presence of indomethacin, 1 mu M, or sodium meclofenamate, 0.1 mu M. 6 The 5-lipoxygenase inhibitors BWA4C, 0.01 to 10 mu M, and L-651,392, 0.01 to 10 mu M, had no effect on LPS-stimulated released or cell-associated IL-1-like activity. Over the same concentration-ranges, neither of the 5-lipoxygenase inhibitors affected released or cell-associated IL-1-like activity in LPS-stimulated mouse macrophages in the presence of indomethacin, 1 mu M. 7 The synthetic diacylglycerol, DiC(8), 10 to 200 mu M, did not itself increase released or cell-associated IL-1-like activity but in the presence of the diacylglycerol kinase inhibitor, R59022, 10 mu M, DiC(8) increased released and cell-associated IL-1-like activity. The activity of DiC(8) on released and cell-associated IL-1-like activity was not increased by indomethacin, 100 mu M. 8 NSAIDs increase LPS-induced cell-associated IL-1-like activity in mouse macrophages by inhibiting the formation of cyclo-oxygenase products such as PGE(2) but at higher concentrations the NSAIDs potentiate LPS-induced release of IL-1-like activity by a mechanism independent of cyclo-oxygenase inhibition. The potentiation of the release of IL-1-like activity appears not to be related to an effect of NSAIDs on either 5-lipoxygenase or diacylglycerol metabolism.