title: Nrf2-dependent repression of interleukin-12 expression in human dendritic cells exposed to inorganic arsenic.
abstract: Inorganic arsenic, a well-known Nrf2 inducer, exerts immunosuppressive properties. In this context, we recently reported that the differentiation of human blood monocytes into immature dendritic cells (DCs), in the presence of low and noncytotoxic concentrations of arsenic, represses the ability of DCs to release key cytokines in response to different stimulating agents. Particularly, arsenic inhibits the expression of human interleukin-12 (IL-12, also named IL-12p70), a major proinflammatory cytokine that controls the differentiation of Th1 lymphocytes. In the present study, we determined if Nrf2 could contribute to these arsenic immunotoxic effects. To this goal, human monocyte-derived DCs were first differentiated in the absence of metalloid and then pretreated with arsenic just before DC stimulation with lipopolysaccharide (LPS). Under these experimental conditions, arsenic rapidly and stably activates Nrf2 and increases the expression of Nrf2 target genes. It also significantly inhibits IL-12 expression in activated DCs, at both mRNA and protein levels. Particularly, arsenic reduces mRNA levels of IL12A and IL12B genes which encodes the p35 and p40 subunits of IL-12p70, respectively. tert-Butylhydroquinone (tBHQ), a reference Nrf2 inducer, mimics arsenic effects and potently inhibits IL-12 expression. Genetic inhibition of Nrf2 expression markedly prevents the repression of both IL12 mRNA and IL-12 protein levels triggered by arsenic and tBHQ in human LPS-stimulated DCs. In addition, arsenic significantly reduces IL-12 mRNA levels in LPS-activated bone marrow-derived DCs from Nrf2+/+ mice but not in DCs from Nrf2-/- mice. Finally, we show that, besides IL-12, arsenic significantly reduces the expression of IL-23, another heterodimer containing the p40 subunit. In conclusion, our study demonstrated that arsenic represses IL-12 expression in human-activated DCs by specifically stimulating Nrf2 activity.
authors: UMR INSERM U1085, Institut de Recherche sur la Santé, l'Environnement et le Travail (IRSET), Université de Rennes 1, Rennes, France.
authors: Mélinda
authors: M
authors: Macoch
authors: UMR INSERM U1085, Institut de Recherche sur la Santé, l'Environnement et le Travail (IRSET), Université de Rennes 1, Rennes, France.
authors: Claudie
authors: C
authors: Morzadec
authors: INSERM, Faculté de Pharmacie, Université Paris Sud, Châtenay-Malabry, France; UniverSud, INSERM, UMR-996 "Cytokines, chemokines and immunopathology", Châtenay-Malabry, France.
authors: Romain
authors: R
authors: Génard
authors: INSERM, Faculté de Pharmacie, Université Paris Sud, Châtenay-Malabry, France; UniverSud, INSERM, UMR-996 "Cytokines, chemokines and immunopathology", Châtenay-Malabry, France.
authors: Marc
authors: M
authors: Pallardy
authors: INSERM, Faculté de Pharmacie, Université Paris Sud, Châtenay-Malabry, France; UniverSud, INSERM, UMR-996 "Cytokines, chemokines and immunopathology", Châtenay-Malabry, France.
authors: Saadia
authors: S
authors: Kerdine-Römer
authors: UMR INSERM U1085, Institut de Recherche sur la Santé, l'Environnement et le Travail (IRSET), Université de Rennes 1, Rennes, France; Pôle Biologie, Centre Hospitalier Universitaire (CHU) Rennes, 2 rue Henri Le Guilloux, 35033 Rennes, France.
authors: Olivier
authors: O
authors: Fardel
authors: UMR INSERM U1085, Institut de Recherche sur la Santé, l'Environnement et le Travail (IRSET), Université de Rennes 1, Rennes, France. Electronic address: laurent.vernhet@univ-rennes1.fr.
authors: Laurent
authors: L
authors: Vernhet
mesh_terms: D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects*; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D034741:RNA, Small Interfering; D018664:Interleukin-12; D001151:Arsenic
keywords: Dendritic cells; Inorganic arsenic; Interleukin-12; Nrf2