LIPOSOMAL PHOSPHATIDYLSERINE INHIBITS TUMOR-CYTOTOXICITY OF LIVER MACROPHAGES INDUCED BY MURAMYL DIPEPTIDE AND LIPOPOLYSACCHARIDE

Liposomes can very efficiently deliver immunomodulators to macrophages so as to induce tumor cytotoxicity. Liposomes most widely used for th at purpose contain negatively charged lipids, in particular phosphatid ylserine (PS), to enhance liposome uptake by the macrophages. We inves tigated the effect of three negatively charged liposomal lipids on the in vitro activation of liver macrophages to tumor cytotoxicity by mur amyl dipeptide (MDP) and lipopolysaccharide (LPS). Both MDP- and LPS-i nduced tumor cytotoxicity towards murine colon adenocarcinoma cells we re strongly inhibited by PS-containing liposomes. Under comparable con ditions phosphatidylglycerol (DPPG)-containing or dicetyl phosphate (D CP)-containing liposomes did not inhibit or only marginally inhibited the induction of tumor cytotoxicity. We did not observe PS-mediated in hibition of tumor cell toxicity when the exposure of the macrophages t o PS-liposomes was limited to the 4-h activation period prior to addit ion of the tumor target cells, suggesting that the inhibitory effect i s accomplished at the level of the later stages of the activation proc ess. Previously, we showed that macrophages which are activated to tum or cytotoxicity during a 24-h incubation with MDP become refractory to a second activation with MDP. Now we observed that simultaneous incub ation with PS-containing liposomes partially prevents this refractorin ess, which is also compatible with an interfering action of PS at a re latively late stage in the activation process. We conclude that PS, de spite its reported stimulatory effect on liposome uptake by macrophage s, can seriously antagonize the effectiveness of immunomodulating, age nts acting on macrophages. This bears relevance to the use of PS-conta ining liposomes as a vehicle for such agents. The results are discusse d in perspective of earlier reported pharmacological effects of PS and its metabolites.