title: Sublethal levels of oxidative stress stimulate transcriptional activation of c-jun and suppress IL-2 promoter activation in Jurkat T cells.
abstract: Sublethal levels of oxidative stress are well known to alter T cell functional responses, but the underlying mechanisms are unknown. The current study examined the effects of oxidative stress on transcriptional activities mediated by c-Fos/c-Jun AP-1 and the nuclear factor of activated T cells (NF-AT). The present results show that Jurkat T cells acutely exposed to micromolar concentrations of H2O2 exhibit substantial increases in AP-1 binding activity and the expression of c-jun but not c-fos mRNA. The preferential induction of c-jun by H2O2 did not represent redox stabilization of mRNA transcripts, and oxidative signals closely resembled PHA/PMA stimulation by effectively transactivating the full length c-jun promoter via the proximal jun1 tumor promoter-responsive element (TRE)-like promoter element. Similarly, the complexes binding the consensus AP-1 TRE and jun TRE-like motifs in cells exposed to oxidative signals or PHA/PMA were indistinguishable, being composed of c-Fos, c-Jun, and JunD. However, PHA/PMA but not oxidative signals induced the coordinate activation of reporter constructs containing the AP-1-TRE, NF-AT, and IL-2 promoter regions along with IL-2 mRNA expression. Furthermore, sublethal levels of H2O2 actively suppressed the transcriptional activation of NF-AT and IL-2 reporters as well as the expression of IL-2 mRNA in cells stimulated with PHA/PMA. Gel shift analysis revealed that oxidative suppression of NF-AT represented inhibition in the early generation of NFAT complexes rather than the binding of preformed NF-AT complexes. These results suggest that oxidative signals can positively and negatively regulate T cell transcriptional events and that changes in cellular redox can uncouple AP-1 regulation of c-jun from transcriptional up-regulation of IL-2 via NF-AT.
authors.affiliation: Department of Medical Biochemistry, William H. Davis Medical Research Center, Ohio State University, Columbus 43210, USA.
authors.forename: L
authors.initials: L
authors.lastname: Beiqing
authors.forename: M
authors.initials: M
authors.lastname: Chen
authors.forename: R L
authors.initials: RL
authors.lastname: Whisler
mesh_terms: D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000235:genetics; D016758:Genes, jun / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000235:genetics*; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D010835:Phytohemagglutinins / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D015533:Transcriptional Activation / Q000276:immunology*; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010835:Phytohemagglutinins; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D006861:Hydrogen Peroxide; D013755:Tetradecanoylphorbol Acetate