Arsenite exposure of cultured airway epithelial cells activates kappaB-dependent interleukin-8 gene expression in the absence of nuclear factor-kappaB nuclear translocation.
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.
Jaspers
I
I
Center for Environmental Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA.
Samet
J M
JM
Reed
W
W
D018053:Arsenites / Q000494:pharmacology*; D001483:Base Sequence; D001665:Binding Sites; D001980:Bronchi; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D017930:Genes, Reporter; D006801:Humans; D020672:I-kappa B Proteins; D015850:Interleukin-6 / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015345:Oligonucleotide Probes; D012333:RNA, Messenger / Q000235:genetics; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D017670:Sodium Compounds / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects* / Q000276:immunology; D014162:Transfection; D017968:Vanadium Compounds / Q000494:pharmacology
D018053:Arsenites; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D015345:Oligonucleotide Probes; D012333:RNA, Messenger; D017670:Sodium Compounds; D017968:Vanadium Compounds; D000072000:NF-KappaB Inhibitor alpha; C017947:sodium arsenite; C034028:vanadyl sulfate