Induction of nitric oxide production and tumoricidal properties in murine macrophages by a new synthetic lipopeptide JBT3002 encapsulated in liposomes.
We studied activation to the tumoricidal state of murine peritoneal macrophages by liposomes containing a new synthetic analogue, JBT3002, of a lipoprotein from the outer wall of a gram-negative bacterium. The liposomes containing JBT3002 or CGP31362 were superior to liposomes containing muramyl tripeptide phosphatidylethanolamine (MTP-PE) for tumoricidal activation in three ways. First, efficient macrophage activation required lower concentrations of JBT3002 or CGP31362 than MTP-PE. Second, macrophage activation by JBT3002 was less dependent on priming by interferon-gamma. Third, MLV-JBT3002 activated tumoricidal properties in both lipopolysaccharide (LPS)-responsive and LPS-nonresponsive macrophages. The activation of tumoricidal properties by MLV-JBP3002 depended on protein tyrosine kinase (PTK) activity associated with phosphorylation of tyrosine. The major mechanism for tumoricidal activity in macrophages incubated with MLV-JBT3002 was due to increased activity of inducible nitric oxide synthase (iNOS) and, hence, production of nitric oxide (NO). We base this conclusion on the results of several experiments. First, MLV-JBT3002 was not directly toxic to tumor target cells. Second, the specific iNOS inhibitor NG-monomethyl-L-arginine abrogated tumor cell lysis by MLV-JBT3002-treated macrophages. Third, macrophages from iNOS knockout mice did not lyse tumor cells, even after incubation with high concentrations of MLV-JBT3002. These data suggest that liposomes containing the synthetic bacterial lipopeptide JBT3002 are potent activators of macrophage tumoricidal properties.
Eue
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Department of Cell Biology, University of Texas, M. D. Anderson Cancer Center, Houston 77030, USA.
Kumar
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R
Dong
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Killion
J J
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Fidler
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IJ
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000031:analogs & derivatives / Q000494:pharmacology; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D005260:Female; D055666:Lipopeptides; D008074:Lipoproteins / Q000494:pharmacology*; D008081:Liposomes; D008262:Macrophage Activation / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010587:Phagocytosis; D010714:Phosphatidylethanolamines / Q000494:pharmacology; D010766:Phosphorylation; D013047:Specific Pathogen-Free Organisms; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D000276:Adjuvants, Immunologic; C112524:JBT-3002; D055666:Lipopeptides; D008074:Lipoproteins; D008081:Liposomes; D009842:Oligopeptides; D010446:Peptide Fragments; D010714:Phosphatidylethanolamines; C037144:mifamurtide; D009569:Nitric Oxide; D014443:Tyrosine; D000119:Acetylmuramyl-Alanyl-Isoglutamine; C068423:CGP 31362; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse