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

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.