Muramyl tripeptide phosphatidylethanolamine encapsulated in liposomes stimulates monocyte production of tumor necrosis factor and interleukin-1 in vitro.
Muramyl tripeptide phosphatidylethanolamine (MTP-PE), a synthetic lipophilic analogue of muramyl dipeptide (MDP), can be incorporated into the lipid membrane of liposomes. Liposomes containing MTP-PE (L-MTP-PE) stimulated monocytes to selectively kill tumors, but not normal cells in vitro. Furthermore, the activation of monocyte tumoricidal function was demonstrated following the i.v. infusion of L-MTP-PE in a phase I trial with cancer patients. The purpose of this study was to determine the mechanism by which L-MTP-PE activates monocytes. Monocyte tumoricidal function is linked to both interleukin-1 (IL-1) and tumor necrosis factor (TNF). Therefore, normal human monocytes were incubated for various times with L-MTP-PE, empty liposomes, or medium in the presence or absence of gamma interferon (IFN-gamma). The supernatants were removed and assayed for TNF and IL-1 using the L929 and D10.G4.1 assays, respectively. TNF was detected after a 4 hr incubation with L-MTP-PE but not with empty liposomes or medium. TNF secretion peaked at 8 hr and was sustained for up to 72 hr. A 4-fold increase in TNF mRNA levels was demonstrated after 8 hr. An increased level of IL-1 beta mRNA was detected after a 4 hr incubation, but only low level IL-1 secretion was detected in monocytes incubated with L-MTP-PE. Adherent monocytes were frozen and thawed to release intracellular IL-1. Intracellular IL-1 was significantly increased in monocytes incubated with L-MTP-PE. Intracellular IL-1 levels peaked by 8 hr and decreased by 72 hr. Activators were then assayed in the presence or absence of IFN-gamma.(ABSTRACT TRUNCATED AT 250 WORDS)
Maeda
M
M
Department of Cell Biology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Knowles
R D
RD
Kleinerman
E S
ES
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000276:Adjuvants, Immunologic; D000818:Animals; D002478:Cells, Cultured; D004337:Drug Carriers; D006801:Humans; D015151:Immunoblotting; D007223:Infant; D007375:Interleukin-1 / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*; D007700:Kinetics; D007739:L Cells; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology*; D008070:Lipopolysaccharides; D008081:Liposomes; D051379:Mice; D010714:Phosphatidylethanolamines / Q000008:administration & dosage / Q000494:pharmacology*; D012313:RNA / Q000032:analysis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*
D000276:Adjuvants, Immunologic; D004337:Drug Carriers; D007375:Interleukin-1; D008070:Lipopolysaccharides; D008081:Liposomes; D010714:Phosphatidylethanolamines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C037144:mifamurtide; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D012313:RNA