Antisense Inhibition of Silica-Induced Tumor Necrosis Factor in Alveolar Macrophages

Details

• Personal Author:
  Castranova, Vincent ; Liang W ; MaJKH ; Rojanasakul Y ; Shi X ; Weissman, David N.
• Description:
  Tumor necrosis factor-alpha (TNFalpha) has been shown to play an important role in the pathogenesis of silicotic fibrosis. In this study, antisense oligonucleotides targeted to TNFalpha mRNA were used to inhibit silica-induced TNFalpha gene expression in alveolar macrophages. To achieve macrophage-specific oligonucleotide delivery, a molecular conjugate consisting of mannosylated polylysine that exploits endocytosis via the macrophage mannose receptor was used. Complexes were formed between the mannosylated polylysine and oligonucleotides and added to the cells in the presence of silica. Enzyme-linked immunoadsorbent assay showed that the complex consisting of the conjugate and antisense oligomer effectively inhibited TNFalpha production, whereas the oligomer alone had much less effect. Reverse transcriptase-polymerase chain reaction analysis revealed that the reduction in TNFalpha secretion was associated with specific ablation of targeted TNFalpha mRNA. The conjugate alone or conjugate complexed with inverted or sense sequence oligonucleotide had no effect. The promoting effect of the conjugate on antisense activity was shown to be due to enhanced cellular uptake of the oligomer via mannose receptor-mediated endocytosis. Cells lacking mannose receptors showed no susceptibility to the conjugate treatment. These results indicate that effective and selective inhibition of macrophage TNFalpha expression can be achieved using the antisense mannosylated polylysine system. [Description provided by NIOSH]
• Subjects:
  Aerosols Carcinogens Cells, Cultured Dust Environmental Monitoring Hazardous Substances Lung Occupational Health Particulate Matter Quartz Respiratory System Safety Silicon Dioxide

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• Keywords:
  Aerosol-particles Alveolar-cells Cell-cultures Cell-damage Dust-exposure Exposure-assessment Exposure-levels Exposure-limits Particulate-dust Quartz-dust Silica-dusts Toxic-materials Toxins

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• ISSN:
  0021-9258
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; 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:
  272
• Issue:
  7
• NIOSHTIC Number:
  nn:20033960
• Citation:
  J Biol Chem 1997 Feb; 272(7):3910-3914
• Contact Point Address:
  Y. Rojanasakul, Dept. of Basic Pharmaceutical Sciences, P.O. Box 9530, West Virginia University, Health Sciences Center, Morgantown, WV 26506
• Email:
  rojan@wvnvaxa.wvnet.edu
• CAS Registry Number:
  Quartz (SiO2) (CAS RN 14808-60-7)
• Federal Fiscal Year:
  1997
• Peer Reviewed:
  True
• Source Full Name:
  Journal of Biological Chemistry
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:2311a3d8218b27ad86884a476de337466528460e7e952b86958fe567bb83e3ea689ee4b31108cf06f40a73c6a0a80e11ef2f088e7586833d497006e8d3127756
• Download URL:
  https://stacks.cdc.gov/view/cdc/189356/cdc_189356_DS1.pdf
• File Type:
  [PDF - 283.19 KB ]