title: Nuclear factor-erythroid 2 (NF-E2) p45-related factor-2 (Nrf2) modulates dendritic cell immune function through regulation of p38 MAPK-cAMP-responsive element binding protein/activating transcription factor 1 signaling.
abstract: Nrf2 is a redox-responsive transcription factor that has been implicated in the regulation of DC immune function. Loss of Nrf2 results in increased co-stimulatory molecule expression, enhanced T cell stimulatory capacity, and increased reactive oxygen species (ROS) levels in murine immature DCs (iDCs). It is unknown whether altered immune function of Nrf2-deficient DCs (Nrf2(-/-) iDCs) is due to elevated ROS levels. Furthermore, it is unclear which intracellular signaling pathways are involved in Nrf2-mediated regulation of DC function. Using antioxidant vitamins to reset ROS levels in Nrf2(-/-) iDCs, we show that elevated ROS is not responsible for the altered phenotype and function of these DCs. Pharmacological inhibitors were used to explore the role of key MAPKs in mediating the altered phenotype and function in Nrf2(-/-) iDCs. We demonstrate that the increased co-stimulatory molecule expression (MHC II and CD86) and antigen-specific T cell activation capacity observed in Nrf2(-/-) iDCs was reversed by inhibition of p38 MAPK but not JNK. Importantly, we provide evidence for increased phosphorylation of cAMP-responsive element binding protein (CREB) and activating transcription factor 1 (ATF1), transcription factors that are downstream of p38 MAPK. The increased phosphorylation of CREB/ATF1 in Nrf2(-/-) iDCs was sensitive to p38 MAPK inhibition. We also show data to implicate heme oxygenase-1 as a potential molecular link between Nrf2 and CREB/ATF1. These results indicate that dysregulation of p38 MAPK-CREB/ATF1 signaling axis underlies the altered function and phenotype in Nrf2-deficient DCs. Our findings provide new insights into the mechanisms by which Nrf2 mediates regulation of DC function.
authors.affiliation: Medical Research Council Centre for Drug Safety Science and Department of Molecular and Clinical Pharmacology, Sherrington Buildings, Ashton Street, University of Liverpool, Liverpool L69 3GE, United Kingdom.
authors.forename: Laith M A
authors.initials: LM
authors.lastname: Al-Huseini
authors.forename: Han Xian
authors.initials: HX
authors.lastname: Aw Yeang
authors.forename: Swaminathan
authors.initials: S
authors.lastname: Sethu
authors.forename: Naif
authors.initials: N
authors.lastname: Alhumeed
authors.forename: Junnat M
authors.initials: JM
authors.lastname: Hamdam
authors.forename: Yulia
authors.initials: Y
authors.lastname: Tingle
authors.forename: Laiche
authors.initials: L
authors.lastname: Djouhri
authors.forename: Neil
authors.initials: N
authors.lastname: Kitteringham
authors.forename: B Kevin
authors.initials: BK
authors.lastname: Park
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Goldring
authors.forename: Jean G
authors.initials: JG
authors.lastname: Sathish
mesh_terms: D051697:Activating Transcription Factor 1 / Q000378:metabolism*; D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D051697:Activating Transcription Factor 1; C497100:Atf1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D016753:Interleukin-10; D051547:Heme Oxygenase-1; D048051:p38 Mitogen-Activated Protein Kinases
keywords: CREB/ATF1; Co-stimulation; Dendritic Cells; Heme Oxygenase; Nrf2; Reactive Oxygen Species (ROS); p38 MAPK