Differential IκB kinase activation and IκBα degradation by Interleukin-1β and tumor necrosis factor-α in human U937 monocytic cells -: Evidence for additional regulatory steps in κB-dependent transcription
Differential IκB kinase activation and IκBα degradation by Interleukin-1β and tumor necrosis factor-α in human U937 monocytic cells -: Evidence for additional regulatory steps in κB-dependent transcription
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DOI：
10.1074/jbc.274.28.19965
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发表时间：
1999-07-09
影响因子：
4.8
通讯作者：
Newton, R
中科院分区：
文献类型：
--
作者：
Nasuhara, Y;Adcock, IM;Newton, R
I κ B激酶（IKK）位于NF-κ B诱导激酶（MK）的下游，并通过I κ B α的磷酸化激活NF-κ B，这导致I κ B α降解和NF-κ B的释放。在U937单核细胞中，白介素（IL）-1 β（1 ng/ml）和肿瘤坏死因子（TNF）-α（10 ng/ml）同等地诱导κ B依赖性转录。然而，IKK活性强烈诱导TNF-α，而不是IL-1 β。这与I κ B α磷酸化和降解一致，但TNF-α诱导的NF-κ B DNA结合仅比IL-1 β高30-40%。这不能用I κ B β、I κ B β或p105的降解或NF-κ B、I κ B α复合物的核转位或NF-κ B的非降解依赖性释放来解释。显性阴性（NIK）抑制TNF-α和IL-1 β诱导的κ B依赖性转录分别为60%和35%。这些数据揭示了IKK激活、I κ B α降解和NF-κ B DNA结合之间的不精确关系，提示存在调节NF-κ B激活的其他机制。最后，DNA结合和转录激活之间缺乏相关性，加上PP 1和染料木黄酮都抑制KB依赖性转录而不影响DNA结合活性的事实，证明NF-κ B DNA结合下游存在调节步骤。这些数据在治疗上是重要的，因为抑制NIK-IKK-I κ B α级联可能不会产生NF-κ B依赖性基因表达的等效降低。
The I kappa B kinases (IKKs) lie downstream of the NF-kappa B-inducing kinase (MK) and activate NF-kappa B by phosphorylation of I kappa B alpha, This leads to I kappa B alpha degradation and release of NF-kappa B, In U937 monocytic cells, interleukin (IL)-1 beta (1 ng/ml) and tumor necrosis factor (TNF)-alpha; 10 ng/ml) induced kappa B-dependent transcription equally. However, IKK activity was strongly induced by TNF-alpha but not by IL-1 beta. This was consistent with I kappa B alpha phosphorylation and degradation, yet TNF-alpha-induced NF-KB DNA binding was only 30-40% greater than for IL-1 beta. This was not explained by degradation of I kappa B beta, I kappa B epsilon, Or p105 nor nuclear translocation of NF-kappa B.I kappa B alpha complexes or degradation-independent release of NF-KB. Dominant negative (NIK) repressed TNF-alpha and IL-1 beta-induced kappa B-ependent transcription by similar to 60% and similar to 35%, respectively. These data reveal an imprecise relationship between IKK activation, I kappa B alpha degradation, and NF-kappa B DNA binding, suggesting the existence of additional mechanisms that regulate NF-kappa B activation. Finally, the lack of correlation between DNA binding and transcriptional activation plus the fact that PP1 and genistein both inhibited KB-dependent transcription without affecting DNA binding activity demonstrate the existence of regulatory steps downstream of NF-kappa B DNA binding. Therapeutically these data are important as inhibition of the NIK-IKK-I kappa B alpha cascade may not produce equivalent reductions in NF-kappa B-dependent gene expression.