Stimulation of macrophage protease secretion via liposomal delivery of muramyl dipeptide derivatives to intracellular sites.
We have observed that murine macrophages can be activated for enhanced neutral protease secretion by exposing the cells to muramyl dipeptides (MDPs). A lipophilic derivative of nor-MDP is more efficacious than the parent hydrophilic nor-MDP. The efficacy and potency of the lipophilic and more prominently the hydrophilic drugs can be increased (10-10(3) fold) by encapsulating them in lipid vesicles (liposomes); however the encapsulation of drug causes a delay in the onset of activation. The enhanced effectiveness of liposomal MDPs seems in part, to be due to increased uptake, slow release and thus potentiated action of the drug at intracellular sites as emphasized by studies with [3H]-MDP. Appropriate distribution of the drug to intracellular compartments of the cell also seems to be an important factor in the activation process. The internalization of a relatively large amounts (greater than 5 ng/10(6) cells) of nor-MDP results in 'down regulation', that is reduced protease secretion, as compared to effects produced by internalization of lesser amounts of the drug. The macrophage activating effects of liposomal MDPs do not seem to require the processing of liposomes in the lysosomal compartment; thus lysosome-blocking agents, such as chloroquine and dextran sulphate, do not affect the induction of protease secretion.
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D008081:Liposomes; D008247:Lysosomes; D008262:Macrophage Activation; D008264:Macrophages / Q000201:enzymology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010447:Peptide Hydrolases / Q000378:metabolism*; D011961:Receptors, Fc
D008081:Liposomes; D011961:Receptors, Fc; D000119:Acetylmuramyl-Alanyl-Isoglutamine; C035295:6-O-stearoyl-N-acetylmuramyl-alanylisoglutamine; D010447:Peptide Hydrolases