title: Intracellular glutathione redox status in human dendritic cells regulates IL-27 production and T-cell polarization.
abstract: BACKGROUND
  Glutathione redox status, changes in intracellular reduced (GSH) or oxidized (GSSG) glutathione, plays a significant role in various aspects of cellular function. In this study, we examined whether intracellular glutathione redox status in human dendritic cells (DCs) regulates the polarization of Th1/Th2 balance.
  
  
  METHODS
  Human monocyte-derived DCs (MD-DCs) treated with glutathione reduced form ethyl ester (GSH-OEt) or L-buthionine-(S,R)-sulfoximine (BSO) were stimulated by lipopolysaccharide (LPS), and the levels of polarization cytokines were measured. Next, DCs matured by LPS or thymic stromal lymphopoietin (TSLP) were cocultured with allogeneic CD4(+) naive T cells and Th1/Th2 balance was evaluated by cytokine production from the primed T cells.
  
  
  RESULTS
  Monocyte-derived DCs exposed to GSH-OEt and BSO had increased and decreased intracellular GSH contents, respectively. Lipopolysaccharide-induced interleukin (IL)-27 production was enhanced by GSH-OEt and suppressed by BSO, but neither GSH-OEt nor BSO affected the expression of HLA-DR, CD80, CD83, or CD86. Mature GSH-OEt-treated MD-DCs enhanced interferon (IFN)-γ production from CD4(+) T cells compared with nontreated MD-DCs, and small interfering RNA (siRNA) against IL-27 suppressed the effect of GSH-OEt on IFN-γ production. Additionally, although human myeloid DCs activated by TSLP (TSLP-DCs) prime naïve CD4(+) T cells to differentiate into Th2 cells, treatment of TSLP-DCs with GSH-OEt reduced IL-13 production and enhanced IFN-γ production by CD4(+) T cells. Interleukin-27 siRNA attenuated the inhibitory effect of GSH-OEt on Th2 polarization.
  
  
  CONCLUSIONS
  Our results reveal that Th1 and Th2 responses are controlled by intracellular glutathione redox status in DCs through IL-27 production.
authors.affiliation: Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kamide
authors.forename: M
authors.initials: M
authors.lastname: Utsugi
authors.forename: K
authors.initials: K
authors.lastname: Dobashi
authors.forename: A
authors.initials: A
authors.lastname: Ono
authors.forename: T
authors.initials: T
authors.lastname: Ishizuka
authors.forename: T
authors.initials: T
authors.lastname: Hisada
authors.forename: Y
authors.initials: Y
authors.lastname: Koga
authors.forename: K
authors.initials: K
authors.lastname: Uno
authors.forename: J
authors.initials: J
authors.lastname: Hamuro
authors.forename: M
authors.initials: M
authors.lastname: Mori
mesh_terms: D002454:Cell Differentiation / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis*; D042541:Intracellular Space / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D010084:Oxidation-Reduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D016207:Cytokines; D020381:Interleukin-17; D008070:Lipopolysaccharides; D005978:Glutathione