title: Vanadium-induced kappaB-dependent transcription depends upon peroxide-induced activation of the p38 mitogen-activated protein kinase.
abstract: Activation of nuclear factor (NF)-kappaB and subsequent proinflammatory gene expression in human airway epithelial cells can be evoked by oxidative stress. In this study we examined signal transduction pathways activated by vanadyl sulfate (V(IV))-induced oxidative stress in normal human bronchial epithelial cells. Both nuclear translocation of NF-kappaB and enhanced kappaB-dependent transcription induced by V(IV) were inhibited by overexpression of catalase, but not Cu,Zn superoxide dismutase (Cu,Zn-SOD), indicating that peroxides rather than superoxides initiated signaling. Catalase selectively blocked the response to V(IV) because it inhibited neither NF-kappaB translocation nor kappaB-dependent transcription evoked by the proinflammatory cytokine tumor necrosis factor (TNF)-alpha. The V(IV)-induced kappaB-dependent transcription was dependent upon activation of the p38 mitogen-activated protein kinase because overexpression of dominant-negative mutants of the p38 MAPK pathway inhibited V(IV)-induced kappaB-dependent transcription. This inhibition was not due to suppression of NF-kappaB nuclear translocation because NF-kappaB DNA binding was unaffected by the inhibition of p38 activity. Overexpression of catalase, but not Cu,Zn-SOD, inhibited p38 activation, indicating that peroxides activated p38. Catalase failed to block V(IV)- induced increases in phosphotyrosine levels, suggesting that the catalase-sensitive signaling components were independent of V(IV)-induced tyrosine phosphorylation. The data demonstrate that V(IV)-induced oxidative stress activates at least two distinct pathways, NF-kappaB nuclear translocation and p38-dependent transactivation of NF-kappaB, both of which are required to fully activate kappaB-dependent transcription. Moreover, V(IV)-induced oxidative stress activated these pathways in bronchial epithelial cells by upstream signaling cascades that were distinct at some level from those used by the proinflammatory cytokine TNF-alpha.
authors.affiliation: Center for Environmental Medicine and Lung Biology, University of North Carolina School of Medicine, Chapel Hill, USA. Ilona_Jaspers@med.unc.edu
authors.forename: I
authors.initials: I
authors.lastname: Jaspers
authors.forename: J M
authors.initials: JM
authors.lastname: Samet
authors.forename: S
authors.initials: S
authors.lastname: Erzurum
authors.forename: W
authors.initials: W
authors.lastname: Reed
mesh_terms: D001980:Bronchi / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010545:Peroxides / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D017968:Vanadium Compounds / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D016328:NF-kappa B; D010545:Peroxides; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D017968:Vanadium Compounds; D019000:Phosphotyrosine; C034028:vanadyl sulfate; D002374:Catalase; D013482:Superoxide Dismutase; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases