Vanadium-induced κB-dependent transcription depends upon peroxide-induced activation of the p38 mitogen-activated protein kinase

Activation of nuclear factor (NF)-kappa B 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-kappa B and enhanced kappa B-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-kappa B translocation nor kappa B-dependent transcription evoked by the proinflammatory cytokine tumor necrosis factor (TNF)-alpha. The V-IV-induced kappa B-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 kappa B-dependent transcription. This inhibition was not due to suppression of NF-kappa B nuclear translocation because NF-kappa B 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-kappa B nuclear translocation and p38-dependent transactivation of NF-kappa B, both of which are required to fully activate kappa B-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.