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Antisense oligodeoxynucleotides targeting internal exon sequences efficiently regulate TNF-alpha expression.

M Mayne1, W Ni, R McKenna

  • 1Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Canada.

Antisense & Nucleic Acid Drug Development
|June 4, 1999
PubMed
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Antisense oligodeoxynucleotides (ODN) targeting exon sequences near splice sites effectively inhibited tumor necrosis factor-alpha (TNF-alpha) gene expression. This approach offers a new strategy for regulating TNF-alpha, a key inflammatory mediator.

Area of Science:

  • Molecular Biology
  • Immunology
  • Gene Regulation

Background:

  • Exon sequences adjacent to splice sites are crucial for mRNA processing.
  • Tumor necrosis factor-alpha (TNF-alpha) is a significant pro-inflammatory cytokine that is difficult to regulate using antisense oligodeoxynucleotides (ODN).

Purpose of the Study:

  • To investigate the efficacy of targeting specific exon sequences with ODN to inhibit TNF-alpha gene expression.
  • To identify optimal target domains within the TNF-alpha gene for antisense-mediated regulation.

Main Methods:

  • Oligodeoxynucleotides (ODN) were designed to target exon sequences upstream of donor splice sites (ORF4, ORF6) and downstream of acceptor splice sites in the TNF-alpha gene.
  • The effect of ODN on TNF-alpha mRNA and protein levels was assessed in stimulated U937 cells, human macrophages, and human peripheral blood mononuclear cells (PBMC).

Related Experiment Videos

  • Dose-dependent responses and specificity were evaluated by measuring levels of TNF-alpha and interleukin-6 (IL-6).

    • Main Results:

    • ODN targeting exon sequences upstream of donor splice sites (ORF4 and ORF6) significantly reduced TNF-alpha levels in U937 cells in a dose-dependent manner.
    • End-phosphorothioated ORF4 (ORF4-PE) demonstrated potent inhibition, reducing TNF-alpha mRNA by over 80% and protein by 60% in U937 cells.
    • ORF4-PE effectively reduced TNF-alpha protein synthesis in various stimulated immune cells, including human macrophages and PBMCs, and murine monocytes.

    Conclusions:

    • Exon sequences flanking donor splice sites represent highly effective target domains for antisense inhibition of TNF-alpha gene expression.
    • Antisense ODN targeting these specific exon regions provide a promising strategy for controlling TNF-alpha-mediated inflammation.