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Blood, Vol. 95 No. 4 (February 15), 2000:
pp. 1249-1257
Targeted disruption of Stat6 DNA binding activity by an
oligonucleotide decoy blocks IL-4-driven TH2 cell response
Li Hua Wang,
Xiao Yi Yang,
Robert A. Kirken,
James H. Resau, and
William L. Farrar
From the Cytokine Molecular Mechanisms Section, Laboratory of
Molecular Immunoregulation, Division of Basic Sciences; the Intramural
Research Support Program, SAIC Frederick, National Cancer
Institute-Frederick Cancer Research and Development Center, Frederick,
MD; the Department of Integrative Biology, Pharmacology, and
Physiology, University of Texas at Houston, TX; and the ABL-Basic
Research Program, National Cancer Institute, Frederick, MD.
The transcription factor, signal transducer and activator of
transcription (Stat) 6, regulates TH2-lymphocyte activity
by controlling the expression and responsiveness to interleukin
(IL)-4, which plays a key role in numerous allergic maladies.
Therefore, we sought to use a phosphorothiolate cis-element decoy to
target disruption of Stat6 transcriptional activity. Here we showed
that the Stat6 decoy potently ablated the messenger RNA expression and
production of IL-4, but not of several other cytokines.
The Stat6 decoy functionally disrupted IL-4-inducible
cell proliferation of murine TH2 cells and primary human
CD4+ T lymphocytes. Specificity of the decoy was
demonstrated by its ability to directly block Stat6 binding to a
cis-element probe and transactivation, but not affect Stat6 tyrosine
phosphorylation or expression of the IL-4 receptor chains. Moreover,
the decoy failed to inhibit non-Stat6-dependent signaling pathways
since IL-2 was competent to induce cell proliferation and activation of
Stats 1, 3, and 5a/b. With the use of laser scanning confocal microscopy, fluorescently tagged Stat6 decoy was detectable in the
cytoplasm and nucleus; however, greater levels of oligonucleotide were
present in the latter following IL-4 treatment. Taken together, these
data suggest that IL-4-driven TH2 cell activity can be
preferentially restricted via targeted disruption of Stat6 by a novel
and specific decoy strategy that may possess gene therapeutic potential.
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