title: Tumor necrosis factor-alpha down-regulates human Cu/Zn superoxide dismutase 1 promoter via JNK/AP-1 signaling pathway.
abstract: Overexpression of Cu/Zn superoxide dismutase 1 (SOD1) in monocytes blocks reactive oxygen species-induced inhibition of cell growth and apoptosis and renders cells resistant to the toxic effect of tumor necrosis factor (TNF)-alpha, suggesting that TNF-alpha represses the SOD1 gene in these cells. We herein show that TNF-alpha decreases SOD1 mRNA, protein, and promoter activity in U937 cells. Electrophoretic mobility-shift assays (EMSA) show that TNF-alpha decreased binding of three different complexes. Ectopic Sp1 overexpression markedly increased SOD1-basal promoter activity and partially antagonized the TNF-alpha inhibitory effect. In contrast, ectopic c-Jun overexpression mimics TNF-alpha inhibitory effects and antagonizes Sp1 stimulatory effects. In agreement with these findings, EMSA shows a TNF-alpha-induced increase in AP-1 and a decrease in Sp1 DNA binding. Disruption of the C/EBP site decreases, whereas mutation in the Sp1/Egr-1 site completely abolishes DNA-binding and promoter activity. A JNK inhibitor antagonized the negative effects of TNF-alpha on SOD1 promoter activity, suggesting that JNK signaling through c-Jun protein activation is critical for the TNF-alpha-dependent SOD1 repression. A greater understanding of the mechanisms of TNF-alpha-induced SOD1 repression could facilitate the design and development of novel therapeutic drugs for inflammatory conditions.
authors.affiliation: INSERM U606, Lariboisiere Hospital, Paris, France.
authors.forename: Valéry
authors.initials: V
authors.lastname: Afonso
authors.forename: Guilherme
authors.initials: G
authors.lastname: Santos
authors.forename: Pascal
authors.initials: P
authors.lastname: Collin
authors.forename: Abdel-Majid
authors.initials: AM
authors.lastname: Khatib
authors.forename: Dragoslav R
authors.initials: DR
authors.lastname: Mitrovic
authors.forename: Noureddine
authors.initials: N
authors.lastname: Lomri
authors.forename: Dale C
authors.initials: DC
authors.lastname: Leitman
authors.forename: Abderrahim
authors.initials: A
authors.lastname: Lomri
mesh_terms: D001483:Base Sequence; D015536:Down-Regulation; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000235:genetics*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D020298:U937 Cells
chemical_list: D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D013482:Superoxide Dismutase; D048670:MAP Kinase Kinase 4