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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.

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HEMATOPOIESIS

Rapid TNFR1-dependent lymphocyte depletion in vivo with a selective chemical inhibitor of IKKbeta

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

From Millennium Pharmaceuticals, Cambridge, MA.

The transcription factor NF-{kappa}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 IKKbeta, an Ikappa-B kinase that regulates NF-{kappa}B. IKKbeta and NF-{kappa}B are required in vivo for prevention of TNF{alpha}-mediated apoptosis. ML120B sensitized mouse bone marrow progenitors and granulocytes, but not mature B cells to TNF{alpha} 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 IKKbeta 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 IKKbeta 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 IKKbeta inhibitors for the treatment of inflammatory disease and cancer.


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