Pharmacological control of leukotriene and prostaglandin production from mouse peritoneal macrophages

Abstract

Leukotriene and prostaglandin production by mouse peritoneal macrophages was investigated. It could be shown that the tumour promoter 12-O-tetradecanoylphorbol-13-acetate initiated the release of prostaglandin E2 but had little effect on the release of leukotriene C4-like immunoreactivity. The divalent cation ionophore A 23187 at concentrations between 10(-6) and 10(-8) mol/l initiated prostaglandin as well as leukotriene release. This prostaglandin and leukotriene release could be modulated by drugs. Non-steroidal anti-inflammatory drugs including benoxaprofen inhibited prostaglandin release but simultaneously enhanced leukotriene production. The analgesics paracetamol and 4-methylaminoantipyrine had similar effects at high concentrations. The experimental compound BW 755 c inhibited prostaglandin and leukotriene production while the antithrombotic compound nafazatrom inhibited the production of leukotriene C4-like immunoreactivity but enhanced prostaglandin E2 production. Nordihydroguaiaretic acid inhibited prostaglandin and leukotriene production. The results show that 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. Our results do not provide evidence that differences in anti-inflammatory activity claimed for some of the drugs tested can 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.

The mechanism of coronary collateral vasoconstriction in response to cyclooxygenase blockade.

“…2 4 Second, cyclooxygenase blockade could result in diversion of arachidonic acid into the lipoxygenase pathway, thereby causing increased leukotriene production with consequent collateral vessel constriction. 5 Finally, a direct vasoconstrictor action, which appears to be independent of cyclooxygenase inhibition, has been reported for indomethacin and might account for the observed findings.6…”

Stimulation of Ciliary Activity by Indomethacin in Rabbit Tracheal Epithelial Organ Culture

“…Sigma), an inhibitor of the lipoxygenase pathway [Brune et al, 1984], for 15 min and chal lenged with indomethacin (3 x 10'1 ' M). Stock solu tions of indomethacin and NDGA were dissolved in ethanol before use.…”

A glycerol ether induces mobilization and 12-lipoxygenation of arachidonic acid in macrophages. Synergistic effect on mobilization and induction of leukotriene C formation by activators of protein kinase C

“…This product also formed when PMA was replaced by 1,2-dioctanoyl-sn-glycerol. Leukotriene C is known to be formed in macrophages responding to zymosan or calcium ionophore [4][5][6] and its formation is throught to require an increase in cytosolic calcium [15]. The total mobilization of arachidonic acid in response to the combination of PMA and 1,2-Ip 3-0-C10 was also greater than that seen with each of the agents separately.…”

“…Figure 3 also depicts a time-dependent increase in the labeling of phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate, which was shown in separate experiments to correspond to relative increases in each phosphoinositide of 50-100 percent (at 20 pM 1,2-Ip 3-0-Ct0). Previous studies in peritoneal macrophages have shown that activators of protein kinase C, such as PMA or 1,2-dioctanoyl-sn-glycerol provoke release of arachidonic acid from the major phospholipids and degradation of phosphatidylinositol by a phospholipase A pathway [1,2], selective formation of prostaglandin E z [4,5,13] and a characteristic pattern of protein phosphorylation [3]. Analysis of individual phospholipids showed that, at variance with the PMA-induced mobilization of arachidonic acid from ethanolamine, choline and inositol phosphoglycerides, the glycerol ether caused virtually no liberation from choline phosphoglycerides (Table I).…”

“…It has also been shown that activators of kinase C, such as 4-fl-phorbo112-myristate 13-acetate (PMA), induce selective formation of prostaglandin E2 in these cells [4,5], while zymosan particles and calcium ionophore promote in addition the formation of leukotriene C [4 6]. Since 1,2-diacyl-sn-glycerols appear to act as physiological regulators of kinase C [7,8] it was considered of interest to investigate whether synthetic glycerol derivatives could either mimick or modulate the signal pathway leading to phospholipase A activation and formation of prostaglandin E2.…”