Rapid TNFR1-dependent lymphocyte depletion in vivo with a selective chemical inhibitor of IKKβ
Rapid TNFR1-dependent lymphocyte depletion in vivo with a selective chemical inhibitor of IKKβ
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DOI：
10.1182/blood-2005-09-3852
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发表时间：
2006-06-01
期刊：
影响因子：
20.3
通讯作者：
Fraser, Christopher C.
中科院分区：
文献类型：
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作者：
Nagashima, Kumiko;Sasseville, Vito G.;Fraser, Christopher C.
转录因子NF-κ B在调节炎症和细胞凋亡中起核心作用，使其成为药物开发的引人注目的靶点。我们鉴定了一种特异性抑制IKK β的小分子抑制剂（ML 120 B），IKK β是一种调节NF-κ B的I κ-B激酶。IKK β和NF-κ B是体内预防TNF α介导的细胞凋亡所必需的。ML 120 B在体外使小鼠骨髓祖细胞和粒细胞（但不使成熟的B细胞）对TNF α杀伤致敏，并在单次口服给药后6小时内在体内诱导骨髓和脾脏细胞凋亡。ML 120 B对IKK β的体内抑制导致骨髓中所有发育阶段的胸腺细胞和B细胞耗竭，但未耗竭粒细胞。TNF受体缺陷型小鼠胸腺细胞和B细胞在体内对ML 120 B诱导的耗竭具有抗性。令人惊讶的是，存活的骨髓粒细胞在用ML 120 B体内给药后表达TNFR 1和TNFR 2。我们的研究结果表明，在体内用小分子抑制IKK β导致T和B细胞的快速TNF依赖性耗竭。这一观察结果对IKK β抑制剂治疗炎症性疾病和癌症的潜在用途有几个意义。
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 IKK beta, an Ikappa-B kinase that regulates NF-kappa B. IKK beta 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 IKK beta 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 beta 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 beta inhibitors for the treatment of inflammatory disease and cancer.