title: Epicubenol and Ferruginol induce DC from human monocytes and differentiate IL-10-producing regulatory T cells in vitro.
abstract: Epicubenol and 19-hydroxyferruginol (Ferruginol) are sesquiterpenes isolated from the black heartwood of Cryptomeria japonica. Dendritic cells (DC) are specialized antigen-presenting cells that monitor the antigenic environment and activate naïve T cells. The role of DC is not only to sense danger but also to tolerize the immune system to antigens encountered in the absence of maturation/inflammatory stimuli. In this study, we attempted to investigate the effects of Epicubenol and Ferruginol on the phenotypic and functional maturation of human monocytes-derived DC in vitro. Human monocytes were cultured with GM-CSF and IL-4 for 6 days under standard conditions, followed by another 2 days with Epicubenol or Ferruginol. The expression levels of CD1a, CD83, and HLA-DR as expressed by mean fluorescence intensity (MFI) on Epicubenol-primed DC or Ferruginol-primed DC were enhanced. Allogeneic Epicubenol-primed DC or Ferruginol-primed DC co-cultured with naïve T cells at 1:5 ratio, secreted IL-10 and TGF-beta, but little IL-4. Moreover, T cells that develop in co-culture of Epicubenol-primed DC or Ferruginol-primed DC and naïve T cells at 1:5 ratio suppressed the proliferation of autologous T cells at Treg cells: Ttarget cells and this suppression of proliferation was inhibited by anti-IL-10 mAb. The expression of FoxP3 mRNA on T cells that develop in co-culture of Epicubenol-primed DC or Ferruginol-primed DC and naïve T cells was lower. From these results, Epicubenol and Ferruginol may induce IL-10-producing Treg 1 cells from naïve T cells by modulating DC function. It seems that Epicubenol and Ferruginol appear to be a target for tolerance after transplantation and in autoimmune diseases.
authors.affiliation: Division of Cellular Allergology, Research Center Borstel, Germany. mtakei@fz-borstel.de
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: D045784:Abietanes; D015703:Antigens, CD / Q000378:metabolism; D018949:Antigens, CD1 / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects*; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics; D000097802:CD83 Antigen
chemical_list: D045784:Abietanes; D015703:Antigens, CD; D018949:Antigens, CD1; D004224:Diterpenes; D051858:Forkhead Transcription Factors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006684:HLA-DR Antigens; D007136:Immunoglobulins; D016753:Interleukin-10; D015847:Interleukin-4; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D012717:Sesquiterpenes; D016212:Transforming Growth Factor beta; D000097802:CD83 Antigen; C419393:CD1a antigen; C418974:FOXP3 protein, human; C506317:epicubenol; C431074:ferruginol