DUAL EFFECTS OF OXIDIZED LOW-DENSITY-LIPOPROTEIN ON IMMUNE-STIMULATEDNITRIC-OXIDE AND PROSTAGLANDIN RELEASE IN MACROPHAGES

Oxidized low-density lipoprotein (LDL) is currently regarded as a tent ative key player in atherosclerosis by virtue of its ability to induce intracellular lipid accumulation and to modulate cell functions in th e vessel wall. We previously demonstrated that inducible nitric oxide (NO) synthase activity is attenuated in lipid-laden J774 macrophages o btained by incubation with oxidized LDL 200 mu g ml(-1) for 24 h. In t he present study we investigated the effect of oxidized LDL in a lower concentration (20 mu g ml(-1)) or for a shorter time (6 h) and the po ssible mediator role of prostaglandin E(2) and prostacyclin. Prostagla ndins and the NO synthase metabolites citrulline and nitrite were elev ated in the 24 h supernatant after immune stimulation with interferon- gamma 100 U ml(-1) with or without lipopolysaccharide 10 mu g ml(-1). Pretreatment with oxidized LDL 20 mu g ml(-1) for 18 h decreased nitri te release by 31 +/- 2%, whereas prostaglandin production was not affe cted. A 6 h pre-exposure to 200 mu g ml(-1) had an opposite effect: it significantly potentiated interferon-gamma-stimulated prostaglandin E (2) (10-fold), prostacyclin (7-fold), nitrite (1.5-fold), and citrulli ne (2.4-fold) release. Indomethacin 10 mu M abolished the prostaglandi n production and largely prevented the oxidized LDL-dependent increase in NO synthase activity. Acetylated LDL was without effect. The data show that the immune-induced release of NO is potentiated or suppresse d, depending on the conditions of exposure to oxidized LDL. The potent iation due to short, high-dose exposure is partly mediated by prostagl andins since indomethacin inhibited both processes.