title: Th2 skewing by activation of Nrf2 in CD4(+) T cells.
abstract: NF erythroid 2-related factor 2 (Nrf2) is a transcription factor that mediates the upregulation of a battery of cytoprotective genes in response to cell stress. Recent studies showed that Nrf2 also modulates immune responses and exhibits anti-inflammatory activity. In this article, we demonstrate that a common food preservative, tert-butylhydroquinone, can activate Nrf2 in T cells, as evidenced by Nrf2 binding to the antioxidant response element and the subsequent upregulation of Nrf2 target genes. The activation of Nrf2 suppresses IFN-γ production, while inducing the production of the Th2 cytokines IL-4, IL-5, and IL-13. Nrf2 activation also suppresses T-bet DNA binding and promotes GATA-binding protein 3 DNA binding. Collectively, the present studies suggested that Nrf2 activation skews CD4(+) T cells toward Th2 differentiation and, thus, represents a novel regulatory mechanism in CD4(+) T cells. Further studies are needed to determine whether the commercial use of Nrf2 activators as food preservatives promotes food allergies in humans.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Cheryl E
authors.initials: CE
authors.lastname: Rockwell
authors.forename: Mingcai
authors.initials: M
authors.lastname: Zhang
authors.forename: Patrick E
authors.initials: PE
authors.lastname: Fields
authors.forename: Curtis D
authors.initials: CD
authors.lastname: Klaassen
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D005512:Food Hypersensitivity; D005520:Food Preservatives / Q000494:pharmacology*; D050990:GATA3 Transcription Factor / Q000378:metabolism; D006873:Hydroquinones / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis; D018793:Interleukin-13 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D015848:Interleukin-5 / Q000096:biosynthesis; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008806:Mice, Inbred AKR; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D000098815:T-bet Transcription Factor
chemical_list: D005520:Food Preservatives; D050990:GATA3 Transcription Factor; D006873:Hydroquinones; D018793:Interleukin-13; D015848:Interleukin-5; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D015847:Interleukin-4; D007371:Interferon-gamma; C018855:2-tert-butylhydroquinone; D008156:Luciferases