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 serum albumin (MBSA) was internalized by macrophages (Mphi) through scavenger receptor (SCR)-mediated endocytosis, which leads to 50-fold higher cytotoxic activity against non-Mphi tumor cells compared with that elicited by free MDP-treated Mphi. The enhanced cytotoxic effect of MBSA-MDP was found to be a result of higher secretion of interleukin (IL)-1, IL-6, tumor necrosis factor alpha (TNF-alpha), and nitric oxide (NO) because the addition of antibodies directed against IL-1, IL-6, or TNF-alpha in combination with Mphi cultures totally abrogated the tumoricidal activity of MBSA-MDP. It is interesting to note that MBSA-MDP triggers the secretion of IL-12, whereas IL-10, a Mphi suppressor cytokine, could be detected only on free MDP treatment. The cytotoxic activity of MBSA-MDP was inhibited by indomethacin, indicating a regulatory role for prostaglandin E2 (PGE2). Efficient SCR-mediated intracellular delivery of MDP leading to elimination of cancer cells suggests the immunotherapeutic potential of this approach for treatment of neoplasia.
Srividya
S
S
National Institute of Immunology, New Delhi, India.
Roy
R P
RP
Basu
S K
SK
Mukhopadhyay
A
A
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000493:pharmacokinetics*; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism* / Q000502:physiology; D003602:Cytotoxicity, Immunologic; D004705:Endocytosis; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D007700:Kinetics; D008262:Macrophage Activation; D008264:Macrophages / Q000502:physiology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology*; D008546:Melanoma, Experimental / Q000503:physiopathology; D051379:Mice; D011971:Receptors, Immunologic / Q000502:physiology*; D051116:Receptors, Scavenger; D012710:Serum Albumin, Bovine / Q000493:pharmacokinetics / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D016207:Cytokines; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; C049877:maleylalbumin; D016753:Interleukin-10; D018664:Interleukin-12; D012710:Serum Albumin, Bovine; D000119:Acetylmuramyl-Alanyl-Isoglutamine