title: T-cadinol and calamenene induce dendritic cells from human monocytes and drive Th1 polarization.
abstract: T-cadinol and calamenene are sesquiterpenes isolated from the heartwood of Cryptomeria japonica and are pharmacologically active substances. Dendritic cells are pivotal in the initiation of adaptive immune responses and are recognized as key to the induction of immune responses to cancer. This study investigated the effects of T-cadinol and calamenene on the phenotypic and functional maturation of human monocyte-derived dendritic cells in vitro. Human monocytes were cultured with recombinant human granulocyte-macrophage colony-stimulation factor (GM-CSF) and recombinant human interleukin-4 (IL-4) for 6 days under standard conditions, followed by another 2 days in the presence of T-cadinol, calamenene, lipopolysaccharide (LPS), CT or nifedipine. Dendritic cells harvested on day 8 were examined using functional assays. The expression levels of CD1a, CD80, CD83, CD86 and HLA-DR on T-cadinol-primed dendritic cells or calamenene-primed dendritic cells were enhanced with a concomitant decrease in endocytic activity. T-cadinol-primed dendritic cells or calamenene-primed dendritic cells also enhanced the T cell stimulatory capacity in an allogeneic mixed lymphocyte reaction, as measured by T cell proliferation. Naïve T cells co-cultured with allogeneic T-cadinol-primed dendritic cells or calamenene-primed dendritic cells at 1:5 dendritic cells/T cell ratio turned into typical Th1 cells which produced large quantities of interferon-gamma (IFN-gamma) and released small amounts of IL-4 depending on IL-12 secretion. In contrast, naïve T cells co-cultured with CT-primed dendritic cells turned into Th2 cells. T-cadinol-primed dendritic cells and calamenene-primed dendritic cells expressed the chemokine receptor CCR7 and had a high migration to macrophage inflammatory protein (MIP-3beta). Intracellular Ca(2+) mobilization in T-cadinol-primed dendritic cells and calamenene-primed dendritic cells was induced by MIP-3beta. The differentiation and functional maturation of human monocyte-derived dendritic cells were not affected by nifedipine. These results suggest that T-cadinol and calamenene may be used in dendritic cells-based immunotherapy for cancer.
authors.affiliation: Division of Cellular Allergology, Research Center Borstel, Parkallee 22, D-23845, Germany. mtakei@pep.ne.jp
authors.forename: Masao
authors.initials: M
authors.lastname: Takei
authors.forename: Akemi
authors.initials: A
authors.lastname: Umeyama
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Arihara
mesh_terms: D000954:Antigens, Surface / Q000096:biosynthesis; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D032485:Cryptomeria / Q000737:chemistry; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D004705:Endocytosis / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D007959:Lymphocyte Culture Test, Mixed; D009000:Monocytes / Q000166:cytology / Q000187:drug effects*; D000081223:Polycyclic Sesquiterpenes; D012333:RNA, Messenger / Q000378:metabolism; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D013729:Terpenes / Q000494:pharmacology*; D018417:Th1 Cells / Q000276:immunology
chemical_list: D000954:Antigens, Surface; C515370:CCR7 protein, human; D016207:Cytokines; D000081223:Polycyclic Sesquiterpenes; D012333:RNA, Messenger; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D013729:Terpenes; C445364:cadinol; C502644:calamenene; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D002118:Calcium