Abrogation of species specificity for activation of tumoricidal properties in macrophages by recombinant mouse or human interferon-γ encapsulated in liposomes

Highly purified human blood monocytes, isolated by continuous Percoll density gradients under endotoxin-free conditions, and mouse peritoneal exudate macrophages (PEM) were activated in vitro by the combination of muramyl dipeptide (MDP) and recombinant interferon-γ (r-IFN-γ) to become tumoricidal against their respective tumorigenic target cells. The activation of human monocytes or mouse PEM by free unencapsulated r-IFN-γ and MDP was species specific: human r-IFN-γ activated human blood monocytes to lyse allogeneic melanoma cells, but did not activate mouse PEM. Mouse r-IFN-γ activated mouse PEM to lyse syngeneic melanoma cells, but did not activate cytotoxic properties in human monocytes. The encapsulation of either mouse or human r-IFN-γ with MDP within the same liposome preparation produced synergistic activation of cytotoxic properties in both PEM and monocytes without apparent species specificity. The activation of tumoricidal properties in macrophages by r-IFN-γ and MDP occurred as a consequence of intracellular interaction. We base this conclusion on the data showing that whereas free r-IFN-γ and MDP did not activate macrophages pretreated with pronase, liposome-encapsulated r-IFN-γ and MDP did. Moreover, the i.v. injection of liposomes containing human or mouse r-IFN-γ and MDP produced in vivo activation of mouse alveolar macrophages. These data suggest that in contrast to activation with free r-IFN-γ, which requires binding to macrophage surface receptors, the intracellular interaction of r-IFN-γ, which produces tumoricidal activity in macrophages, is not species specific.