title: Bryostatin-1 enhances the maturation and antigen-presenting ability of murine and human dendritic cells.
abstract: In this study, we investigated the effect of bryostatin-1 (Bryo-1), an antineoplastic agent, on dendritic cell (DC) maturation, activation, and functions. Murine bone marrow-derived DCs on culture with Bryo-1 alone, Bryo-1 + calcium ionophore (CI), but not CI alone exhibited morphologic changes characteristic of mature DCs and expressed increased levels of CD40, CD80, and CD86. Moreover, Bryo-1 + CI-treated DCs exhibited enhanced antigen-presenting ability to naive and antigen-specific T cells and alloreactive T cells. Bryo-1 + CI-mediated activation of DCs involved protein kinase C (PKC), especially PKC-alpha, -delta, and -iota, and addition of PKC inhibitors impaired their ability to activate T cells. Bryo-1 + CI treatment of DCs did not activate mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase, p38 MAPK, or stress-activated protein kinase/c-Jun NH2-terminal kinase pathways. Finally, treatment of DCs with Bryo-1 alone and Bryo-1 + CI, but not CI alone, induced nuclear translocation of nuclear factor kappaB as studied by confocal microscopy. DCs generated from human peripheral blood monocytes or from human cord blood CD34+ hematopoietic stem cells, when cultured with Bryo-1 + CI, also showed maturation and increased T-cell stimulatory activity. Bryo-1 + CI was more potent in inducing maturation and activation of DCs when compared with other agents such as tumor necrosis factor alpha, lipopolysaccharide, or phorbol 12-myristate 13-acetate + CI. Collectively, the current study shows for the first time that Bryo-1 alone or in combination with CI may promote the maturation of DCs and therefore may be useful in development of DC-based cancer immunotherapy.
authors.affiliation: Department of Microbiology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
authors.forename: Yoonkyung
authors.initials: Y
authors.lastname: Do
authors.forename: Venkatesh L
authors.initials: VL
authors.lastname: Hegde
authors.forename: Prakash S
authors.initials: PS
authors.lastname: Nagarkatti
authors.forename: Mitzi
authors.initials: M
authors.lastname: Nagarkatti
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects*; D054713:Bryostatins; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology*; D005260:Female; D005312:Fetal Blood / Q000166:cytology; D006801:Humans; D007527:Isoenzymes; D048031:JNK Mitogen-Activated Protein Kinases; D007783:Lactones / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D048670:MAP Kinase Kinase 4; D018942:Macrolides; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D054713:Bryostatins; D007527:Isoenzymes; D007783:Lactones; D018942:Macrolides; D016328:NF-kappa B; C046785:bryostatin 1; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases