Dual effects of oxidized low-density lipoprotein on immune-stimulated nitric oxide and prostaglandin release in macrophages.
Oxidized low-density lipoprotein (LDL) is currently regarded as a tentative key player in atherosclerosis by virtue of its ability to induce intracellular lipid accumulation and to modulate cell functions in the vessel wall. We previously demonstrated that inducible nitric oxide (NO) synthase activity is attenuated in lipid-laden J774 macrophages obtained by incubation with oxidized LDL 200 micrograms ml-1 for 24 h. In the present study we investigated the effect of oxidized LDL in a lower concentration (20 micrograms ml-1) or for a shorter time (6 h) and the possible mediator role of prostaglandin E2 and prostacyclin. Prostaglandins and the NO synthase metabolites citrulline and nitrite were elevated in the 24 h supernatant after immune stimulation with interferon-gamma 100 U ml-1 with or without lipopolysaccharide 10 micrograms ml-1. Pretreatment with oxidized LDL 20 micrograms ml-1 for 18 h decreased nitrite release by 31 +/- 2%, whereas prostaglandin production was not affected. A 6 h pre-exposure to 200 micrograms ml-1 had an opposite effect: it significantly potentiated interferon-gamma-stimulated prostaglandin E2 (10-fold), prostacyclin (7-fold), nitrite (1.5-fold), and citrulline (2.4-fold) release. Indomethacin 10 microM abolished the prostaglandin 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 suppressed, depending on the conditions of exposure to oxidized LDL. The potentiation due to short, high-dose exposure is partly mediated by prostaglandins since indomethacin inhibited both processes.
Matthys
K E
KE
Division of Pharmacology, University of Antwerp (UIA), Wilrijk, Belgium.
Van Hove
C E
CE
Jorens
P G
PG
Rosseneu
M
M
Marescau
B
B
Herman
A G
AG
Bult
H
H
D000818:Animals; D002478:Cells, Cultured; D002956:Citrulline / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D010084:Oxidation-Reduction; D011453:Prostaglandins / Q000096:biosynthesis* / Q000494:pharmacology
D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; D009573:Nitrites; D011453:Prostaglandins; D002956:Citrulline; D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D007213:Indomethacin