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Dendritic Cell Maturation Induced by Muramyl Dipeptide (MDP) Derivatives: Monoacylated MDP Confers TLR2/TLR4 Activation¹

Junji Uehori^,¶, Koichi Fukase, Takashi Akazawa, Satoshi Uematsu, Shizuo Akira, Kenji Funami^*, Masashi Shingai^*, Misako Matsumoto^*,,¶, Ichiro Azuma^||, Kumao Toyoshima, Shoichi Kusumoto^2, and Tsukasa Seya^3,*,,¶

^* Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan; Department of Immunology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, and Department of Chemistry, Graduate School of Science, Osaka University, Osaka, Japan; ^¶ Department of Molecular Immunology, Nara Institute for Science and Technology, Nara, Japan; and ^|| Hakodate National College of Technology, Hakodate, Japan

6-O-acyl-muramyldipeptides (MDP) with various lengths of fatty acid chains were examined for their dendritic cell (DC) maturation activity expressed through TLRs. Judging from anti-TLR mAb/inhibitor-blocking analysis, MDP derivatives with a single octanoyl or stearoyl fatty acid chain were found to activate TLR2 and TLR4 on human DCs, although intact and diacylated MDP expressed no ability to activate TLRs. Human DC activation profiles by the monoacylated MDP were essentially similar to those by Calmette-Guérin (BCG)-cell wall skeleton (CWS) and BCG-peptidoglycan (PGN) based on their ability to up-regulate costimulators, HLA-DR, ₂-microglobulin, and allostimulatory MLR. Monoacylated MDP induced cytokines with similar profiles to BCG-CWS or -PGN, although their potency for induction of TNF-, IL-12p40, and IL-6 was less than that of BCG-CWS or -PGN. The MDP derivatives initiated similar activation in normal mouse macrophages, but exhibited no effect on TLR2/4-deficient or MyD88-deficient mouse macrophages. Mutation of D-isoGln to L-isoGln in monoacylated MDP did not result in loss of the DC maturation activity, suggesting marginal participation of nucleotide-binding oligomerization domain 2, if any, in monoacyl MDP-dependent DC maturation. These results define the adjuvant activity of 6-O-acyl MDP compounds at the molecular level. They target TLR2/TLR4 and act through the MyD88-dependent pathway in DCs and macrophages. Hence, the unusual combined activation of TLR2 and TLR4 observed with Mycobacterium tuberculosis is in part reflected in the functional properties of monoacylated MDP compounds. These findings infer that the essential minimal requirement for TLR2/4-mediated adjuvancy of BCG lies within a modified MDP.

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