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Blood, 1 June 2006, Vol. 107, No. 11, pp. 4266-4273. Prepublished online as a Blood First Edition Paper on January 26, 2006; DOI 10.1182/blood-2005-09-3852. This Article Full Text (PDF) All Versions of this Article: 2005-09-3852v1 107/11/4266    most recent Alert me when this article is cited Alert me if a correction is posted 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 Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Nagashima, K. Articles by Fraser, C. C Search for Related Content PubMed PubMed Citation Articles by Nagashima, K. Articles by Fraser, C. C Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 26, 2005 Accepted January 18, 2006 Rapid TNFR1 dependent lymphocyte depletion in vivo with a selective chemical inhibitor of IKK Kumiko Nagashima, Vito G Sasseville, Danyi Wen, Andrew Bielecki, Hua Yang, Chris Simpson, Ethan Grant, Michael Hepperle, Gerry Harriman, Bruce Jaffee, Tim Ocain, Yajun Xu, and Christopher C Fraser* Millennium Pharmaceuticals, Inc., Cambridge, MA, USA * Corresponding author; email: fraser{at}mpi.com. The transcription factor NF-B plays a central role in regulating inflammation and apoptosis making it a compelling target for drug development. We identified a small molecule inhibitor (ML120B) that specifically inhibits IKK, an Ikappa-B kinase that regulates NF-B. IKK and NF-B are required in vivo for prevention of TNF mediated apoptosis. ML120B sensitized mouse bone marrow progenitors and granulocytes, but not mature B-cells to TNF killing in vitro, and induced apoptosis in vivo in the bone marrow and spleen within 6 hours of a single oral dose. In vivo inhibition of IKK with ML120B resulted in depletion of thymocytes and B-cells in all stages of development in the bone marrow, but did not deplete granulocytes. TNF-receptor deficient mouse thymocytes and B-cells were resistant to ML120B induced depletion in vivo. Surprisingly surviving bone marrow granulocytes expressed TNFR1 and TNFR2, after dosing in vivo with ML120B. Our results show that inhibition of IKK with a small molecule in vivo leads to rapid TNF-dependent depletion of T and B-cells. This observation has several implications for potential use of IKK inhibitors for the treatment of inflammatory disease and cancer. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. 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