PMID- 22311972 OWN - NLM STAT- MEDLINE DCOM- 20120516 LR - 20220310 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 287 IP - 13 DP - 2012 Mar 23 TI - Loss of transcription factor nuclear factor-erythroid 2 (NF-E2) p45-related factor-2 (Nrf2) leads to dysregulation of immune functions, redox homeostasis, and intracellular signaling in dendritic cells. PG - 10556-10564 LID - S0021-9258(20)65464-3 [pii] LID - 10.1074/jbc.M111.322420 [doi] AB - Dendritic cells (DCs) are critical mediators of immunity and immune tolerance by orchestrating multiple aspects of T cell activation and function. Immature DCs (iDCs) expressing low levels of co-stimulatory receptors are highly efficient at antigen capture but are poor activators of T cells. Maturation of DCs is associated with increased expression of co-stimulatory molecules. Co-stimulatory receptor gene expression is regulated by intracellular redox, NF-kappaB, and MAPK pathways and by histone deacetylase (HDAC) activity. The transcription factor, Nrf2, is important for maintaining intracellular glutathione (GSH) levels and redox homeostasis and has been implicated in modulating DC co-stimulatory receptor expression. It is unclear whether Nrf2 mediates this effect by GSH-dependent mechanisms and whether it influences DC signaling pathways. Using bone marrow-derived iDCs from Nrf2(+/+) and Nrf2(-/-) mice, we demonstrate that Nrf2(-/-) iDCs have lower basal GSH levels, enhanced co-stimulatory receptor expression, impaired phagocytic functions, and increased antigen-specific CD8 T cell stimulation capacity. Interestingly, lowering GSH levels in Nrf2(+/+) iDCs did not recapitulate the Nrf2(-/-) iDC phenotype. Loss of Nrf2 resulted in elevated basal levels of reactive oxygen species but did not affect basal NF-kappaB activity or p38 MAPK phosphorylation. Using pharmacological inhibitors, we demonstrate that enhanced co-stimulatory receptor phenotype of Nrf2(-/-) iDC does not require ERK activity but is dependent on HDAC activity, indicating a potential interaction between Nrf2 function and HDAC. These results suggest that Nrf2 activity is required to counter rises in intracellular reactive oxygen species and to regulate pathways that control DC co-stimulatory receptor expression. FAU - Yeang, Han Xian Aw AU - Yeang HXA AD - Department of Pharmacology, Medical Research Council Centre for Drug Safety Science, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE, United Kingdom. FAU - Hamdam, Junnat M AU - Hamdam JM AD - Department of Pharmacology, Medical Research Council Centre for Drug Safety Science, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE, United Kingdom. FAU - Al-Huseini, Laith M A AU - Al-Huseini LMA AD - Department of Pharmacology, Medical Research Council Centre for Drug Safety Science, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE, United Kingdom. FAU - Sethu, Swaminathan AU - Sethu S AD - Department of Pharmacology, Medical Research Council Centre for Drug Safety Science, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE, United Kingdom. FAU - Djouhri, Laiche AU - Djouhri L AD - Department of Pharmacology, Medical Research Council Centre for Drug Safety Science, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE, United Kingdom. FAU - Walsh, Joanne AU - Walsh J AD - Department of Pharmacology, Medical Research Council Centre for Drug Safety Science, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE, United Kingdom. FAU - Kitteringham, Neil AU - Kitteringham N AD - Department of Pharmacology, Medical Research Council Centre for Drug Safety Science, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE, United Kingdom. FAU - Park, B Kevin AU - Park BK AD - Department of Pharmacology, Medical Research Council Centre for Drug Safety Science, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE, United Kingdom. FAU - Goldring, Christopher E AU - Goldring CE AD - Department of Pharmacology, Medical Research Council Centre for Drug Safety Science, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE, United Kingdom. Electronic address: chrissy@liv.ac.uk. FAU - Sathish, Jean G AU - Sathish JG AD - Department of Pharmacology, Medical Research Council Centre for Drug Safety Science, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE, United Kingdom. Electronic address: Jean.Sathish@liv.ac.uk. LA - eng GR - G0700420/MRC_/Medical Research Council/United Kingdom GR - WT_/Wellcome Trust/United Kingdom GR - G0700654/MRC_/Medical Research Council/United Kingdom GR - BB_/Biotechnology and Biological Sciences Research Council/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20120206 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (NF-E2-Related Factor 2) RN - 0 (NF-kappa B) RN - 0 (Nfe2l2 protein, mouse) RN - 0 (Reactive Oxygen Species) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) RN - EC 3.5.1.98 (Histone Deacetylases) RN - GAN16C9B8O (Glutathione) SB - IM MH - Animals MH - CD8-Positive T-Lymphocytes/metabolism MH - Dendritic Cells/cytology/*metabolism MH - Glutathione/genetics/metabolism MH - Histone Deacetylases/genetics/metabolism MH - Homeostasis/*physiology MH - MAP Kinase Signaling System/*physiology MH - Mice MH - Mice, Knockout MH - NF-E2-Related Factor 2/genetics/*metabolism MH - NF-kappa B/genetics/metabolism MH - Oxidation-Reduction MH - Reactive Oxygen Species/*metabolism MH - p38 Mitogen-Activated Protein Kinases/genetics/metabolism PMC - PMC3322986 EDAT- 2012/02/09 06:00 MHDA- 2012/05/17 06:00 PMCR- 2012/02/06 CRDT- 2012/02/08 06:00 PHST- 2012/02/08 06:00 [entrez] PHST- 2012/02/09 06:00 [pubmed] PHST- 2012/05/17 06:00 [medline] PHST- 2012/02/06 00:00 [pmc-release] AID - S0021-9258(20)65464-3 [pii] AID - M111.322420 [pii] AID - 10.1074/jbc.M111.322420 [doi] PST - ppublish SO - J Biol Chem. 2012 Mar 23;287(13):10556-10564. doi: 10.1074/jbc.M111.322420. Epub 2012 Feb 6.