Inhibition of lymphokine-induced macrophage microbicidal activity against Leishmania major by liposomes: characterization of the physicochemical requirements for liposome inhibition.
Resident peritoneal macrophages from untreated mice develop potent microbicidal activity against amastigotes of Leishmania major after in vitro treatment with lymphokine (LK) from mitogen-stimulated spleen cells. LK-induced macrophage microbicidal activity was completely and selectively abrogated by treatment with phosphatidylcholine-phosphatidylserine (PC/PS) liposomes. Other macrophage effector functions (phagocytosis, tumoricidal activity) were unaffected, as was cytotoxicity by macrophages activated in vivo or by LK in vitro before liposome treatment. Activation factors in LK were not adsorbed or destroyed by liposomes. Liposome-induced inhibition was unaffected by indomethacin and was fully reversible: macrophages washed free of liposomes developed strong microbicidal activity with subsequent LK treatment. Changes in liposomal lipid composition markedly altered suppressive effects, but inhibition was not dependent on liposome size, cholesterol content, charge, or number of lamellae. Liposomes composed of PC alone or in combination with any of five different phospholipids were not suppressive. In contrast, inhibition was directly dependent on PS concentration within PC/PS liposomes. Phosphoserine was not inhibitory nor was dimyristoyl PS (synthetic saturated PS). However, the lysophospholipid metabolite of PS, lysoPS, was strongly suppressive. These studies suggest that the reversible and selective inhibition of LK-induced macrophage microbicidal activity by PC/PS liposomes is mediated by PS and its lysoPS metabolite.
D000818:Animals; D007893:Leishmania donovani; D007895:Leishmania tropica; D008081:Liposomes / Q000494:pharmacology*; D008222:Lymphokines / Q000494:pharmacology*; D008246:Lysophospholipids; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010713:Phosphatidylcholines / Q000494:pharmacology; D010718:Phosphatidylserines / Q000494:pharmacology*
D008081:Liposomes; D008222:Lymphokines; D008246:Lysophospholipids; D010713:Phosphatidylcholines; D010718:Phosphatidylserines; C025059:lysophosphatidylserine