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ARSENITE ACTIVATES KB-DEPENDENT IL-8 GENE EXPRESSION IN AIRWAY EPITHELIM IN THE ABSENCE OF NUCLEAR TRANSLOCATION OF NF-KB
Jaspers, I., J M. Samet, AND W. Reed. ARSENITE ACTIVATES KB-DEPENDENT IL-8 GENE EXPRESSION IN AIRWAY EPITHELIM IN THE ABSENCE OF NUCLEAR TRANSLOCATION OF NF-KB. JOURNAL OF BIOLOGICAL CHEMISTRY 274(43):31025-31033.
Airway epithelial cells respond to certain environmental stresses by mounting a proinflammatory response, which is characterized by enhanced synthesis and release of the neutrophil chemotactic and activating factor interleukin-8 (IL-8). IL-8 expression is regulated at the transcriptional level in part by the transcription factor nuclear factor (NF)-kappaB. We compared intracellular signaling mediating IL-8 gene expression in bronchial epithelial cells cultured in vitro and exposed to two inducers of cellular stress, sodium arsenite (As(III)), and vanadyl sulfate (V(IV)). Unstimulated bronchial epithelial cells expressed IL-8, and exposure to both metal compounds significantly enhanced IL-8 expression. Overexpression of a dominant negative inhibitor of NF-kappaB depressed both basal and metal-induced IL-8 expression. Low levels of nuclear NF-kappaB were constitutively present in unstimulated cultures. These levels were augmented by exposure to V(IV), but not As(III). Accordingly, V(IV) induced IkappaBalpha breakdown and NF-kappaB nuclear translocation, whereas As(III) did not. However, both As(III) and V(IV) enhanced kappaB-dependent transcription. In addition, As(III) activation of an IL-8 promoter-reporter construct was partially kappaB-dependent. These data suggested that As(III) enhanced IL-8 gene transcription independently of IkappaB breakdown and nuclear translocation of NF-kappaB in part by enhancing transcription mediated by low levels of constitutive nuclear NF-kappaB.