PHARMACOLOGICAL CONTROL OF LEUKOTRIENE AND PROSTAGLANDIN PRODUCTION FROM MOUSE PERITONEAL-MACROPHAGES

Leukotriene and prostaglandin [PG] production by mouse peritoneal macrophages was investigated. The tumor promoter 12-O-tetradecanoylphorbol-13-acetate initiated the release of PGE2 but had little effect on the release of leukotriene C4-like immunoreactivity. The divalent cation ionophore calcimycin [A 23187] at concentrations between 10-6 and 10-8 mol/l initiated PG as well as leukotriene release. This PG and leukotriene release could be modulated by drugs. Non-steroidal anti-inflammatory drugs including benoxaprofen inhibited PG release but simultaneously enhanced leukotriene production. The analgesics paracetamol and 4-methylaminoantipyrine had similar effects at high concentrations. The experimental compound 3 amino 1-[meta-(trifluoromethyl)-phenyl]-2-pyrazoline [BW 755c] inhibited PG and leukotriene production while the antithrombotic compound nafazatrom inhibited the production of leukotriene C4-like immunoreactivity but enhanced PGE2 production. Nordihydroguaiaretic acid inhibited PG and leukotriene production. The metabolism of arachidonic acid in macrophages via the cyclooxygenase or the lipoxygenase pathway is dependent on the stimulus applied. Both pathways can be inhibited conjointly or selectively by drugs. Differences in anti-inflammmatory activity claimed for some of the drugs tested can not be explained by differential inhibition of either pathway. The experimental system described may be used for assessing the potency of drugs to inhibit the lipoxygenase and the cyclooxygenase pathway of arachidonic acid metabolism.