Skip directly to search Skip directly to A to Z list Skip directly to page options Skip directly to site content

NIOSHTIC-2 Publications Search

Search Results

Antisense inhibition of silica-induced tumor necrosis factor in alveolar macrophages.

Authors
Rojanasakul-Y; Weissman-DN; Shi-X; Castranova-V; Ma-JKH; Liang-W
Source
J Biol Chem 1997 Feb; 272(7):3910-3914
NIOSHTIC No.
20033960
Abstract
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.
Keywords
Aerosol-particles; Toxic-materials; Toxins; Exposure-assessment; Exposure-levels; Exposure-limits; Alveolar-cells; Dust-exposure; Cell-damage; Cell-cultures; Particulate-dust; Carcinogens; Silica-dusts; Quartz-dust
Contact
Y. Rojanasakul, Dept. of Basic Pharmaceutical Sciences, P.O. Box 9530, West Virginia University, Health Sciences Center, Morgantown, WV 26506
CODEN
JBCHA3
CAS No.
14808-60-7
Publication Date
19970201
Document Type
Journal Article
Email Address
rojan@wvnvaxa.wvnet.edu
Fiscal Year
1997
NTIS Accession No.
NTIS Price
Issue of Publication
7
ISSN
0021-9258
NIOSH Division
HELD
Source Name
Journal of Biological Chemistry
State
WV
TOP