Abstract
Glutathione redox status, changes in intracellular reduced (GSH) or oxidized (GSSG) glutathione, plays a significant role in cellular function. We examined whether intracellular glutathione redox status in human dendritic cells (DCs) regulates the production of polarizing signals, such as IL-27, IL-12, and Th1/Th2 responses.
Human PBMCs were obtained from healthy adult volunteers, and monocyte-derived DCs (MD-DCs) were generated from PBMCs. MD-DCs treated with glutathione reduced form ethyl ester (GSH-OEt) or L-buthionine-(S,R)-sulfoximine (BSO) were stimulated by LPS, and the levels of Th1 and Th2 cytokines were measured. Then, DCs matured by LPS or TSLP were cocultured with allogeneic CD4(+) naive T cells and Th1/Th2 balance was evaluated.
Monocyte-derived DCs exposed to GSH-OEt and BSO had increased and decreased intracellular GSH contents, respectively. LPS-induced IL-27 and IL-12 production was enhanced by GSH-OEt and suppressed by BSO. Mature GSH-OEt-treated MD-DCs enhanced interferon (IFN)-γ production from CD4(+) T cells compared with nontreated MD-DCs, and siRNA against IL-27 and anti-IL-12 mAb suppressed the effect of GSH-OEt on IFN-γ production. 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 p28 siRNAs and anti-IL-12 mAb attenuated the inhibitory effect of GSH-OEt on Th2 polarization.
These results indicate that Th1 and Th2 balance are controlled by intracellular glutathione redox status in DCs through the production of IL-27 and IL-12.
- © 2012 ERS
