Asbestos Induction of Nuclear Transcription Factors and Interleukin 8 Gene Regulation

Details

• Personal Author:
  Luster MI ; Simeonova PP
• Description:
  Proinflammatory cytokines and chemotactic peptides are strongly implicated as mediators of the pathophysiologic responses of asbestosis and other chronic inflammatory lung diseases. Recent studies in our laboratory have demonstrated that asbestos fibers stimulate lung epithelial cells to produce interleukin-8 (IL-8), the major neutrophil chemoattractant in the lung. The mechanisms by which asbestos regulates IL-8 expression were studied using the pulmonary type II-like epithelial cell line A549. Membrane permeable hydroxyl scavengers inhibited asbestos induced IL-8 expression. Using A549 cells transfected with the -546 IL-8 construct linked to a chloramphenicol acetyl transferase reporter gene, we have shown that these antioxidants directly inhibited asbestos-stimulated IL-8 promoter-dependent transcription. Asbestos fibers as well as reactive oxygen species generating systems hypoxanthine-xanthine oxidase and hydrogen peroxide stimulated DNA binding activity to the regulatory elements in the IL-8 promoter, binding sites of nuclear factor (NF)-kappaB- and NF-IL-6-like transcription factors. Asbestos-inducible DNA binding activity was partially inhibited by tetramethylthiourea, a hydroxyl radical scavenger. IL-8 secretion was also suppressed by staurosporine, an inhibitor of protein kinase C, and by inhibitors of tyrosine kinase such as herbimycin A and genistein. The suppression paralleled the effect of these inhibitors on asbestos-induced DNA binding to the NF- kappaB- and NF-IL-6-like binding sites of the IL-8 promoter. Taken together, the results suggest that asbestos-induced redox changes and phosphorylation events, mediated by staurosporine-sensitive and tyrosine kinase(s), activate nuclear proteins which recognize the NF- kappaB/NF-IL-6 binding sites of the IL-8 promoter and contribute to the regulation of IL-8 gene expression. [Description provided by NIOSH]
• Subjects:
  Asbestos Chronic Disease Dust Inorganic Chemicals Occupational Health Safety
• Keywords:
  Asbestos-dust Asbestos-fibers Chronic-degenerative-diseases Chronic-inflammation Cytotoxins Dust-exposure Dust-particles Fibrous-dusts Gene-mutation Genotoxic-effects
• ISSN:
  1044-1549
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  North Carolina ; OSHA Region 3 ; OSHA Region 4 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  15
• Issue:
  6
• NIOSHTIC Number:
  nn:20034000
• Citation:
  Am J Respir Cell Mol Biol 1996 Dec; 15(6):787-795
• Contact Point Address:
  Dr. Petia Simeonova, Toxicology and Molecular Biology Branch, HELD, NIOSH, 1095 Willowdale Rd., Morgantown, WV 26505
• CAS Registry Number:
  Asbestos (CAS RN 1332-21-4)
• Federal Fiscal Year:
  1997
• Peer Reviewed:
  True
• Source Full Name:
  American Journal of Respiratory Cell and Molecular Biology
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:aa10376e290d04d70d49c73f630f8e8651b1d920b7ecaa42483e823217d227fecf8ac66b520f7350523b36404b303a3d8a7aeb8665aee814bb5975e4fca49fbd
• Download URL:
  https://stacks.cdc.gov/view/cdc/189391/cdc_189391_DS1.pdf
• File Type:
  [PDF - 1003.65 KB ]