title: Nrf2 expression and activity in human T lymphocytes: stimulation by T cell receptor activation and priming by inorganic arsenic and tert-butylhydroquinone.
abstract: The transcription factor nuclear factor-erythroid 2-related-2 (Nrf2) controls cellular redox homeostasis and displays immunomodulatory properties. Nrf2 alters cytokine expression in murine T cells, but its effects in human T lymphocytes are unknown. This study investigated the expression and activity of Nrf2 in human activated CD4(+) T helper lymphocytes (Th cells) that mediate the adaptive immune response. Th cells were isolated from peripheral blood mononuclear cells and activated with antibodies against CD3 and CD28, mimicking physiologic Th cell stimulation by dendritic cells. Nrf2 is hardly detectable in unstimulated Th cells. Activation of Th cells rapidly and strongly increases the levels of Nrf2 protein by increasing NRF2 gene transcription. Th cell activation also enhances mRNA and protein levels of Nrf2 target genes encoding antioxidant enzymes. Blocking Nrf2 expression using chemical inhibitors or siRNAs prevents these gene inductions. Pretreatment with inorganic arsenic, a Nrf2 inducer that does not alter NRF2 gene expression, increases protein level and transcriptional activity of Nrf2 induced by Th cell stimulation. Inorganic arsenic enhances nuclear translocation of Nrf2, its interaction with the coactivator protein p300, and its DNA binding activity. Inhibition of Nrf2 expression abrogates the effects of inorganic arsenic on mRNA levels of antioxidant genes, but does not alter the expression of IL-2, TNF-α, interferon-γ, or IL-17 in Th cells activated in the absence or presence of the metalloid. In conclusion, this study demonstrates for the first time that stimulation of human Th cells increases transcription of the NRF2 gene and activity of the Nrf2 protein. However, modulation of Nrf2 levels does not modify the secretion of inflammatory cytokines from these T lymphocytes.
authors.affiliation: UMR INSERM U1085, Institut de Recherche sur la Santé, l׳Environnement et le Travail, Université de Rennes 1, 35043 Rennes, France.
authors.forename: Claudie
authors.initials: C
authors.lastname: Morzadec
authors.affiliation: UMR INSERM U1085, Institut de Recherche sur la Santé, l׳Environnement et le Travail, Université de Rennes 1, 35043 Rennes, France.
authors.forename: Mélinda
authors.initials: M
authors.lastname: Macoch
authors.affiliation: UMR INSERM U1085, Institut de Recherche sur la Santé, l׳Environnement et le Travail, Université de Rennes 1, 35043 Rennes, France.
authors.forename: Lydie
authors.initials: L
authors.lastname: Sparfel
authors.affiliation: UMR INSERM U996, Université Paris XI, 92296 Châtenay-Malabry, France.
authors.forename: Saadia
authors.initials: S
authors.lastname: Kerdine-Römer
authors.affiliation: UMR INSERM U1085, Institut de Recherche sur la Santé, l׳Environnement et le Travail, Université de Rennes 1, 35043 Rennes, France; Pôle Biologie, Centre Hospitalier Universitaire Rennes, 35033 Rennes, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Fardel
authors.affiliation: UMR INSERM U1085, Institut de Recherche sur la Santé, l׳Environnement et le Travail, Université de Rennes 1, 35043 Rennes, France. Electronic address: laurent.vernhet@univ-rennes1.fr.
authors.forename: Laurent
authors.initials: L
authors.lastname: Vernhet
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001151:Arsenic / Q000494:pharmacology*; D018106:CD28 Antigens / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism; D020381:Interleukin-17 / Q000096:biosynthesis / Q000378:metabolism; D007376:Interleukin-2 / Q000096:biosynthesis / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D051267:NF-E2-Related Factor 2 / Q000819:agonists / Q000235:genetics* / Q000276:immunology; D021381:Protein Transport; D012333:RNA, Messenger / Q000819:agonists / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D017252:CD3 Complex; D006873:Hydroquinones; D020381:Interleukin-17; D007376:Interleukin-2; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; C018855:2-tert-butylhydroquinone; D050880:p300-CBP Transcription Factors; D001151:Arsenic
keywords: Antioxidant genes; Arsenic; Cytokines; Free radicals; Nrf2; T lymphocytes