Inhibitory effects of diclofenac and indomethacin on interleukin-1-induced changes in PGE2 release. A novel effect on free arachidonic acid levels in human synovial cells.
The inhibitory effects of two non-steroidal anti-inflammatory drugs (NSAIDS), diclofenac and indomethacin, on interleukin-1 (IL-1)-induced changes in arachidonic acid (AA) release and prostaglandin E2(PGE2) production by human synovial cells was investigated. Both diclofenac and indomethacin potently inhibited IL-1 alpha-induced PGE2 release, with IC50 values of 1.6 +/- 0.02 nM and 5.5 +/- 0.1 nM, respectively. A novel effect on IL-1 alpha-mediated changes in AA levels was observed using cells labelled with radioactive AA. Both drugs at micromolar concentrations (10-30 microM) showed an apparent inhibition of IL-1 alpha-induced increases in radioactivity associated with free AA. Concomitant with this inhibition, there was an increase in radioactivity associated with phosphatidylethanolamine (PE) and triglyceride (TG). As the drugs had no effect on IL-1 alpha-induced decreases in radioactivity associated with phosphatidylcholine (PC), this result was interpreted as being due to an enhanced acylation of AA into PE and TG. These results suggest that whilst at nanomolar concentrations, diclofenac and indomethacin can inhibit IL-1 alpha-induced PGE2 output, at micromolar concentrations an effect on free AA levels is also evident. This may have consequences for the release of other mediators such as leukotrienes, whose synthesis also involves the level of free AA.
O'Neill
L A
LA
Department of Pharmacology, Royal College of Surgeons, London, U.K.
Lewis
G P
GP
D000210:Acute-Phase Reaction / Q000378:metabolism; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D002478:Cells, Cultured; D004008:Diclofenac / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism*
D001095:Arachidonic Acids; D007375:Interleukin-1; D004008:Diclofenac; D016718:Arachidonic Acid; D015232:Dinoprostone; D007213:Indomethacin