title: Reactivity of chemical sensitizers toward amino acids in cellulo plays a role in the activation of the Nrf2-ARE pathway in human monocyte dendritic cells and the THP-1 cell line.
abstract: Allergic contact dermatitis resulting from skin sensitization is an inflammatory skin disease linked to the use of chemicals termed haptens. Chemical reactivity is necessary for a chemical to be a sensitizer, allowing both covalent binding to proteins and maturation of dendritic cells (DCs) by mimicking "danger signals." The aim of this study was to evaluate how the reactivity of chemical sensitizers toward amino acids translates into a biological response using the activation of the nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway, which was assessed by the induction of three Nrf2 target genes (ho-1, nqo1, and il-8) and Nrf2 protein accumulation. Nrf2 activation is known to play a role in numerous detoxification mechanisms that could regulate danger signal outcomes in myeloid cells. Monocyte-derived DCs and THP-1 cells were exposed to (a) haptens with cysteine, lysine, or cysteine/lysine reactivity, (b) pro-/prehaptens, and (c) nonsensitizing molecules with reducing or oxidative properties (17 molecules in total). Chemicals were classified as "Nrf2 pathway activators" when at least two Nrf2 target genes associated with Nrf2 protein expression were induced. Results showed that most chemical sensitizers having cysteine and cysteine/lysine affinities were inducers of the Nrf2 pathway in both cell models, whereas lysine-reactive chemicals were less efficient. In THP-1 cells, the Nrf2 pathway was also activated by pro-/prehaptens. Regression analysis revealed that ho-1 and nqo1 expressions were found to be associated with chemical sensitizer reactivity to cysteine, providing evidence of the importance of chemical reactivity, as a part of danger signals, in DC biology.
authors.affiliation: INSERM UMR-S 996, Faculté de Pharmacie, UniverSud, 92290 Châtenay-Malabry, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Migdal
authors.forename: Jérémie
authors.initials: J
authors.lastname: Botton
authors.forename: Zeina
authors.initials: Z
authors.lastname: El Ali
authors.forename: Marie-Eliane
authors.initials: ME
authors.lastname: Azoury
authors.forename: Joan
authors.initials: J
authors.lastname: Guldemann
authors.forename: Elena
authors.initials: E
authors.lastname: Giménez-Arnau
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Lepoittevin
authors.forename: Saadia
authors.initials: S
authors.lastname: Kerdine-Römer
authors.forename: Marc
authors.initials: M
authors.lastname: Pallardy
mesh_terms: D000485:Allergens / Q000737:chemistry* / Q000633:toxicity; D000596:Amino Acids / Q000737:chemistry*; D061745:Antioxidant Response Elements; D002460:Cell Line; D003545:Cysteine / Q000737:chemistry; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression; D006241:Haptens / Q000737:chemistry; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000485:Allergens; D000596:Amino Acids; D006241:Haptens; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D003545:Cysteine
keywords: Nrf2; chemical sensitizer reactivity; dendritic cells.