Dynamic protein associations define two phases of IL-1beta transcriptional activation.
Dynamic protein associations define two phases of IL-1beta transcriptional activation.
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DOI：
10.4049/jimmunol.181.1.503
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发表时间：
2008-07-01
期刊：
影响因子：
--
通讯作者：
Nikolajczyk BS
中科院分区：
文献类型：
--
作者：
Zhang Y;Saccani S;Shin H;Nikolajczyk BS
IL-1β是一种重要的促炎细胞因子，在多种疾病中发挥作用。单核细胞将IL-1β启动子包装成一个“平衡结构”，其特征是无组蛋白转录起始位点和组成性转录因子关联。在LPS刺激下，多种蛋白可诱导与IL-1β基因相关。为了了解组成型和诱导型转录因子的复杂组合如何从平衡结构激活IL-1β基因，我们测量了NF-κB和IFN调节因子（IRF）与IL-1β调节元件关联的时间变化。NF-κB p65亚基的关联在单核细胞刺激后30-60分钟达到峰值，并且在IRF-4募集到IL-1β增强子和最大mRNA产生之前不久。相反，IRF-8/增强子的关联在刺激后减少。为了测试延迟IRF-4/增强子关联的重要性，我们引入了一种突变的PU.1蛋白，该蛋白被证明可以阻止PU.1介导的IRF-4募集到增强子序列。突变的PU.1最初升高IL-1β mRNA，刺激后2-3小时mRNA水平下降。综上所述，这些数据支持IL-1β转录激活的动态模型，其中IRF-8和p65的组合驱动IL-1β转录的初始阶段，而pu .1介导的IRF-4募集到增强子对第二阶段很重要。我们进一步证明NF-κB和IRF-4的激活都依赖于CK2激酶的活性。由于IRF-4/增强子关联需要CK2而不需要p65激活，我们得出结论，CK2独立触发IRF-4和p65通路，作为IL-1β转录的主要调节剂。
IL-1β is a key proinflammatory cytokine with roles in multiple diseases. Monocytes package the IL-1β promoter into a “poised architecture” characterized by a histone-free transcription start site and constitutive transcription factor associations. Upon LPS stimulation, multiple proteins inducibly associate with the IL-1β gene. To understand how the complex combination of constitutive and inducible transcription factors activate the IL-1β gene from a poised structure, we measured temporal changes in NF-κB and IFN regulatory factor (IRF) association with IL-1β regulatory elements. Association of the p65 subunit of NF-κB peaks 30–60 min post-monocyte stimulation, and it shortly precedes IRF-4 recruitment to the IL-1β enhancer and maximal mRNA production. In contrast, IRF-8/enhancer association decreases poststimulation. To test the importance of delayed IRF-4/enhancer association, we introduced a mutated PU.1 protein shown to prevent PU.1-mediated IRF-4 recruitment to the enhancer sequence. Mutated PU.1 initially increased IL-1β mRNA followed by decreased mRNA levels 2–3 h poststimulation. Taken together, these data support a dynamic model of IL-1β transcriptional activation in which a combination of IRF-8 and p65 drives the initial phase of IL-1β transcription, while PU.1-mediated IRF-4 recruitment to the enhancer is important for the second phase. We further demonstrate that activation of both NF-κB and IRF-4 depends on CK2 kinase activity. Because IRF-4/enhancer association requires CK2 but not p65 activation, we conclude that CK2 triggers the IRF-4 and p65 pathways independently to serve as a master regulator of IL-1β transcription.
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