SECRETION PATTERN OF THE RAT-LIVER MACROPHAGE POPULATION FOLLOWING ACTIVATION WITH LIPOSOMAL MURAMYL DIPEPTIDE IN-VIVO AND IN-VITRO

Incubation of rat liver macrophages in vitro with free or liposome-enc apsulated muramyl dipeptide (N-acetylmuramyl-L-alanyl-D-isoglutamine; MDP) resulted in a rapid but transient release of tumor necrosis facto r-alpha (TNF-alpha), followed by a slow, steady release of nitric oxid e (NO) and prostaglandin (PG) E. The secretion pattern induced in situ was determined by isolating the liver macrophages at 2, 12, 24, 48, a nd 72 h after injection of liposomal MDP and measuring the amounts of products secreted in a 24-h period following isolation. TNF-alpha secr etion was detected only in macrophages isolated as early as 2 h after injection of liposomal MDP and not at later time points. Considerable heterogeneity was observed among macrophages of different size: For ex ample, the large-sized cells were far more potent in TNF secretion tha n the smaller cells. Nitric oxide secretion, on the other hand, was ma intained over a full 24-h period following MDP administration and was virtually independent of macrophage size. With regard to PGE release, similar to TNF-alpha secretion, considerable differences in secretory activity between cells of different size were observed. Also in this c ase the large cells were several times more active than the small cell s. In contrast to TNF, however, PGE secretion could be detected up to 24 h after injection of liposomal MDP. These findings support the noti on that the development and maintenance of the activated state of live r macrophages, induced by immunomodulators such as liposomal MDP, are under the control of a complex network of regulatory functions and tha t multiple secretory products play a role in the observed macrophage-m ediated cytotoxicity.