Enhanced maturation and functional capacity of monocyte-derived immature dendritic cells by the synthetic immunomodulator Murabutide.
Murabutide is a safe synthetic immunomodulator derived from muramyl dipeptide, the smallest bioactive unit of bacterial peptidoglycan. Although it is well known that muramyl peptides modulate the functions of monocytes/macrophages, their activity on dendritic cells is poorly documented. We thus investigated the effects of Murabutide on immunophenotype, endocytosis, T-cell stimulatory capacity, and cytokine secretion of human monocyte-derived immature dendritic cells (iDCs). We found that Murabutide triggers immunophenotypic changes as upon treatment, iDCs up-regulate the surface expression of the major histocompatibility complex type II molecule human leucocyte antigen-DR, the co-stimulatory molecules CD80, CD86 and CD40 and the differentiation marker CD83, and down-regulate the expression of the mannose receptor. These phenotypic changes are also mirrored by changes in their biological activity. Subsequent to treatment with the synthetic immunomodulator, DC have a decreased endocytic capacity but exhibit enhanced stimulatory capacity for both allogeneic and autologous T cells. In addition, Murabutide-stimulated iDCs have a greater cytostatic activity toward the tumour cell line THP-1. Furthermore, in the presence of Murabutide, DCs transiently increased the release of macrophage inhibitory protein-1 beta, tumour necrosis factor-alpha and interleukin-10, whereas the enhanced production of macrophage-colony stimulating factor was sustained over the 3-day period analysed. In addition, Murabutide triggers the phosphorylation of the three classes of mitogen-activated protein kinases in iDCs. Altogether our results demonstrate that Murabutide triggers the maturation and activation of monocyte-derived iDCs. As this immunomodulator is approved for administration in humans, it could be a useful adjunct to boost the efficacy of DC-based vaccines designed against tumours or virus-infected cells.
Vidal
V
V
Laboratory of Molecular Immunology of Infection and Inflammation, Institut Pasteur de Lille, France.
Dewulf
J
J
Bahr
G M
GM
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D017951:Antigen Presentation / Q000187:drug effects; D015703:Antigens, CD / Q000378:metabolism; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D004705:Endocytosis / Q000187:drug effects; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D007959:Lymphocyte Culture Test, Mixed; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D016207:Cytokines; D006684:HLA-DR Antigens; D000119:Acetylmuramyl-Alanyl-Isoglutamine; C033575:murabutide; D020928:Mitogen-Activated Protein Kinases