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J. Biol. Chem., Vol. 276, Issue 15, 11759-11765, April 13, 2001
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,,
From the Elevated levels of IgE are intimately
associated with a number of allergic diseases, such as allergic
rhinitis or asthma. Therefore, prevention of IgE production in human
B-cells represents an attractive therapeutic target. IL-4-induced IgE
germline gene transcription represents a crucial early step during IgE
isotype switch differentiation. Gene induction is orchestrated by the coordinated action of the transcription factors STAT6 (signal transducer and activator of transcription), NF- Department of Allergic Diseases, Novartis
Research Institute, Brunnerstrasse 59, A-1230 Vienna, Austria,
§ Novartis Pharma Research, 4002 Basel, Switzerland, and
¶ Respiratory Diseases, Novartis Horsham Research Centre,
Horsham RH12 5AB, United Kingdom
B, PU.1, and C/EBP. This study shows that 2'-aminoethoxy-modified oligonucleotides, which
partially overlap with the STAT6 and the adjacent PU.1/NF-B binding
site, inhibit DNA binding of all three proteins with high affinity in a
dose- and time-dependent fashion in vitro. Loss of protein binding correlated strongly with increasing DNA triplex formation. Importantly, the oligomers also effectively displaced pre-bound recombinant NF-B p50 from double-stranded DNA in
vitro. Functionally, the oligonucleotides led to a selective
inhibition of IL-4-induced reporter gene activity from a construct
driven by the IgE germline gene promoter in human B-cells. These data confirm the critical role of this cytokine-responsive regulatory region
in IgE germline gene induction and further support the concept of
specific modulation of gene expression by DNA triplex formation induced
with chemically modified oligonucleotides.
To whom correspondence should be addressed. Tel.:
43-186634-730; Fax: 43-186634-582; E-mail:
max.woisetschlaeger@pharma.novartis.com.
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