title: A synthetic NOD2 agonist, muramyl dipeptide (MDP)-Lys (L18) and IFN-β synergistically induce dendritic cell maturation with augmented IL-12 production and suppress melanoma growth.
abstract: BACKGROUND
  A synthetic NOD2 agonist, muramyl dipeptide (MDP)-Lys (L18), mimics the bacterial peptidoglycan moiety and acts as a powerful adjuvant that induces cell-mediated immunity.
  
  
  OBJECTIVE
  To investigate the induction of antitumor immune response for malignant melanoma by IFN-β in combination with MDP-Lys (L18) (IFN-MDP-Lys (L18)).
  
  
  METHODS
  Human monocyte-derived DCs (MoDCs) are stimulated with IFN-MDP-Lys (L18) in vitro. We assess the expression of costimulatory molecules on MoDCs by FACS. Moreover, we investigate the induction of Th1 cytokines by real time PCR and ELISA. Further to confirm the anti tumor immune response of IFN-MDP-Lys (L18) therapy, we examine the growth of B16F10 melanoma in vivo.
  
  
  RESULTS
  The stimulation of human MoDCs with IFN-MDP-Lys (L18) significantly augmented the production of IL-12p70, TNF-α, and IL-6 compared to that with MDP or that with IFN-β alone. IFN-MDP-Lys (L18) increased the expression of IL-12p35, IL-12p40, IL-10, TNF-α, IL-6 and IL-1β mRNA by MoDC using real-time PCR. The expression of CD83 and costimulatory molecules CD40, CD80, and CD86 was also augmented in MoDC treated with IFN-MDP-Lys (L18), which resulted in their augmented allogeneic T cell stimulation. In vivo, the administration of IFN-MDP-Lys (L18) significantly suppressed the growth of B16F10 melanoma, while the monotherapy of IFN-β or MDP-Lys (L18) did not significantly affect the tumor growth.
  
  
  CONCLUSIONS
  These findings suggest that IFN-MDP-Lys (L18) can be a promising adjuvant therapy for malignant melanoma.
authors.affiliation: Department of Dermatology, Tohoku University Graduate School of Medicine, Seiryo-machi 1-1, Aoba-ku, Sendai 980-8574, Japan. tfujimura1@mac.com
authors.forename: Taku
authors.initials: T
authors.lastname: Fujimura
authors.forename: Kenshi
authors.initials: K
authors.lastname: Yamasaki
authors.forename: Takanori
authors.initials: T
authors.lastname: Hidaka
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Ito
authors.forename: Setsuya
authors.initials: S
authors.lastname: Aiba
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D049109:Cell Proliferation; D002469:Cell Separation; D003713:Dendritic Cells / Q000166:cytology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis; D016899:Interferon-beta / Q000378:metabolism*; D018664:Interleukin-12 / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy*; D008546:Melanoma, Experimental / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology; D053473:Nod2 Signaling Adaptor Protein / Q000819:agonists / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000097802:CD83 Antigen
chemical_list: D000119:Acetylmuramyl-Alanyl-Isoglutamine; D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D007136:Immunoglobulins; D016899:Interferon-beta; D018664:Interleukin-12; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D053473:Nod2 Signaling Adaptor Protein; D014409:Tumor Necrosis Factor-alpha; D000097802:CD83 Antigen; C429018:NOD2 protein, human; C036866:romurtide