Relationship between NO-synthase activity and TNF-alpha secretion in mouse macrophage lines stimulated by a muramyl peptide entrapped in nanocapsules.
The present study evaluates the ability of a new drug carrier: nanocapsules of poly(D,L-lactide) containing muramyldipeptide-L-alanyl-cholesterol (MTP-Chol NC) to induce activation of mouse macrophage cell lines. MTP-Chol NC stimulated nitric oxide (NO) expression and tumor necrosis factor-alpha (TNF-alpha) production, these are two important mediators of macrophage-mediated cytotoxicity. The encapsulated form was more effective than free muramyldipeptide, at low immunomodulator concentrations. The dose-response curves were completely different for NO and TNF-alpha, implying different regulatory mechanisms. In RAW 264.7 cells, the addition of anti-TNF-alpha antibodies during the activation period did not affect the level of nitrite induced by MTP-Chol Nc and lipopolysaccharide. Therefore, autocrine stimulation by TNF-alpha did not contribute to NO production. On the other hand, the presence of an NO synthase inhibitor led to an increase in TNF-alpha secretion. In J774.A1 cells, which were activated by MTP-Chol NC and interferon-gamma, TNF-alpha production seemed to act as a second messenger. Thus, under certain conditions, NO can play a role in modulating the cytotoxic activities of mouse macrophages.
Seyler
I
I
URA-CNRS 1218, Faculty of Pharmacy, Chatenay-Malabry, France.
Appel
M
M
Devissaguet
J P
JP
Legrand
P
P
Barratt
G
G
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D002214:Capsules; D002478:Cells, Cultured; D006020:Glycopeptides / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D009112:Muramic Acids / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000276:Adjuvants, Immunologic; D002214:Capsules; D006020:Glycopeptides; D008070:Lipopolysaccharides; D009112:Muramic Acids; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D007770:L-Lactate Dehydrogenase; D019001:Nitric Oxide Synthase