Inhibition of interferon gamma-induced macrophage microbicidal activity against Leishmania major by liposomes: inhibition is dependent upon composition of phospholipid headgroups and fatty acids.
Multilamellar liposomes of phosphatidylcholine and phosphatidylserine at a 7:3 molar ratio significantly inhibited activation of murine resident peritoneal macrophages by recombinant murine interferon-gamma for cytotoxicity against amastigotes of the protozoan parasite Leishmania major; other macrophage effector functions, such as particle phagocytosis or tumoricidal activity, were unaffected. This inhibition was not due to direct toxic effects of liposomes against parasite or macrophage, was fully reversible, and was directed at one or more early events in macrophage-LK interactions which ultimately induce microbicidal activity. Liposomes containing some natural phospholipids (phosphatidylserine, phosphatidylethanolamine, phosphatidic acid or diphosphatidyl glycerol), but not phosphatidylcholine, phosphatidylglycerol, or several synthetic saturated phospholipids, prevented the induction of macrophage microbicidal activity. Inhibition by liposomes of various composition was not related to the efficiency with which these vesicles were ingested by macrophages. Inhibitory activity was directly influenced by changes in the phospholipid head group, as well as by the number of unsaturated bonds in phospholipid fatty acids: for a given phospholipid in liposomes, inhibition was directly related to the number of unsaturated bonds among the fatty acids. These data support a role for phospholipids in postbinding regulation of macrophage activation and add to our understanding of how liposome delivery systems can be designed to avoid potential microbicidal suppressive effects.
Gilbreath
M J
MJ
Department of Immunology, Walter Reed Army Institute of Research, Washington, DC 20307-5100.
Fogler
W E
WE
Swartz
G M
GM
Alving
C R
CR
Meltzer
M S
MS
D000818:Animals; D005227:Fatty Acids / Q000032:analysis*; D007371:Interferon-gamma / Q000494:pharmacology*; D007895:Leishmania tropica / Q000276:immunology*; D008081:Liposomes / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010587:Phagocytosis / Q000187:drug effects*; D010741:Phospholipases A / Q000502:physiology; D010743:Phospholipids / Q000032:analysis*
D005227:Fatty Acids; D008081:Liposomes; D010743:Phospholipids; D007371:Interferon-gamma; D010741:Phospholipases A