title: The Nrf2 activator tBHQ inhibits T cell activation of primary human CD4 T cells.
abstract: The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates a battery of antioxidant, detoxification, and cell stress genes. It is activated by oxidative stress and a number of exogenous compounds, one of which is tert-butylhydroquinone (tBHQ), a widely used food preservative. Nrf2 modulates immune responses in numerous rodent models of inflammation, but its effects on human immune cells are not well characterized. The purpose of these studies was to evaluate the effects of the Nrf2 activator tBHQ on early events of T cell activation in primary human cells. Treatment with tBHQ induced mRNA expression of the Nrf2 target genes HMOX-1, GCLC, and NQO1, and also increased NRF2 mRNA expression, albeit to a lesser extent than the other target genes. tBHQ decreased production of the cytokines IL-2 and IFN-γ at both the protein and mRNA levels after stimulation with anti-CD3/anti-CD28 in human peripheral blood mononuclear cells and to an even greater extent in isolated CD4 T cells. Likewise, tBHQ decreased induction of CD25 and CD69 in peripheral blood mononuclear cells (PBMCs) and this decrease was even more marked in isolated CD4 T cells. In addition, tBHQ inhibited induction of NFκB DNA binding in anti-CD3/anti-CD28-activated PBMCs. Collectively, these data suggest that tBHQ inhibits activation of primary human CD4 T cells, which correlates with activation of Nrf2 and inhibition of NFκB DNA binding. Although these studies suggest the food additive tBHQ negatively impacts T cell activation, further studies will be needed to fully elucidate the effect of tBHQ on human immune responses.
authors.affiliation: Department of Pharmacology and Toxicology, Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, USA. Electronic address: turleyal@msu.edu.
authors.forename: Alexandra E
authors.initials: AE
authors.lastname: Turley
authors.affiliation: Cellular and Molecular Biology Program, Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, USA. Electronic address: zagorsk4@msu.edu.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Zagorski
authors.affiliation: Department of Pharmacology and Toxicology, Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, USA; Cellular and Molecular Biology Program, Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, USA. Electronic address: rockwelc@msu.edu.
authors.forename: Cheryl E
authors.initials: CE
authors.lastname: Rockwell
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D000975:Antioxidants / Q000378:metabolism; D018106:CD28 Antigens / Q000737:chemistry; D017252:CD3 Complex / Q000737:chemistry; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D006873:Hydroquinones / Q000737:chemistry*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008213:Lymphocyte Activation; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D011485:Protein Binding; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000975:Antioxidants; D018106:CD28 Antigens; D017252:CD3 Complex; D016207:Cytokines; D004247:DNA; D006873:Hydroquinones; D053645:Interleukin-2 Receptor alpha Subunit; D037181:Lectins, C-Type; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D000099192:CD69 Antigens; C495635:NFE2L2 protein, human; C018855:2-tert-butylhydroquinone
keywords: CD4 T Cells; Human PBMC; Nrf2; tBHQ