Scavenger receptor-mediated delivery of muramyl dipeptide activates antitumor efficacy of macrophages by enhanced secretion of tumor-suppressive cytokines

We showed that muramyl dipeptide (MDP) conjugated to maleylated bovine seru m albumin (MBSA) was internalized by macrophages (M phi) through scavenger receptor (SCR)-mediated endocytosis, which leads to 50-fold higher cytotoxi c activity against non-M phi tumor cells compared with that elicited by fre e MDP-treated M phi. The enhanced cytotoxic effect of MBSA-MDP was found to be a result of higher secretion of interleukin (IL)-1, IL-6, tumor necrosi s factor alpha (TNF-alpha), and nitric oxide (NO) because the addition of a ntibodies directed against IL-1, IL-6, or TNF-alpha in combination with M p hi cultures totally abrogated the tumoricidal activity of MBSA-MDP. It is i nteresting to note that MBSA-MDP triggers the secretion of IL-12, whereas I L-10, a M phi suppressor cytokine, could be detected only on free MDP treat ment. The cytotoxic activity of MBSA-MDP was inhibited by indomethacin, ind icating a regulatory role for prostaglandin E-2 (PGE(2)), Efficient SCR-med iated intracellular delivery of MDP leading to elimination of cancer cells suggests the immunotherapeutic potential of this approach for treatment of neoplasia.