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J. Biol. Chem., Vol. 276, Issue 15, 11759-11765, April 13, 2001

This Article Full Text Full Text (PDF) All Versions of this Article: 276/15/11759    most recent M010260200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Stütz, A. M. Articles by Woisetschläger, M. Search for Related Content PubMed PubMed Citation Articles by Stütz, A. M. Articles by Woisetschläger, M. Social Bookmarking                      What's this?

Inhibition of Interleukin-4- and CD40-induced IgE Germline Gene Promoter Activity by 2'-Aminoethoxy-modified Triplex-forming Oligonucleotides^*

Adrian M. Stütz, Jutta Hoeck, Francois Natt^§, Bernard Cuenoud^¶, and Maximilian Woisetschläger

From the  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

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-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.

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