IL-10 disrupts the Brd4-docking sites to inhibit LPS-induced CXCL8 and TNF-α expression in monocytes: Implications for chronic obstructive pulmonary disease
IL-10 disrupts the Brd4-docking sites to inhibit LPS-induced CXCL8 and TNF-α expression in monocytes: Implications for chronic obstructive pulmonary disease
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DOI：
10.1016/j.jaci.2015.04.023
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发表时间：
2015-09-01
影响因子：
14.2
通讯作者：
Bazzoni, Flavia
中科院分区：
文献类型：
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作者：
Castellucci, Monica;Rossato, Marzia;Bazzoni, Flavia
背景：众所周知，IL-10能够阻断多种促炎细胞因子的表达和产生，从而防止过度或慢性免疫激活的发展。il -10诱导的CXCL8和TNFA基因的转录抑制包括两个不同的阶段：早期阶段，以蛋白质合成不依赖的方式快速发生，其次是第二阶段，更延迟并依赖于蛋白质合成。目的：我们试图确定IL-10快速直接抑制lps诱导的CXCL8和tnf - α转录的机制，这些转录在病理条件下可能存在缺陷。方法：采用染色质免疫沉淀法研究IL-10在lps活化单核细胞CXCL8和TNFA位点引发的分子事件。结果：IL-10抑制lps诱导的CXCL8和tnf - α表达的共同机制是靶向lps诱导的核因子κ B p65丝氨酸276残基（pS(276)p65）磷酸化。结果，所有发生在CXCL8和TNFA位点的pS(276)p65依赖性事件持续减少，最终导致转录物伸长减少。此外，IL-10通过组蛋白去乙酰化酶（HDAC） 2依赖性共价染色质修饰选择性地控制CXCL8转录延伸，破坏转录机制的组装。值得注意的是，来自急性期慢性阻塞性肺疾病患者的pbmc，其HDAC2表达水平可以忽略不计，在抑制CXCL8表达方面几乎不受IL-10的影响。结论：本研究提供了IL-10创造染色质环境降低CXCL8和tnf - α对toll样受体4激活信号的转录率的机制证据。数据确定了治疗策略的新分子靶点，旨在抑制慢性阻塞性肺疾病等病理中的炎症，其中描述了细胞内HDAC2水平降低。
Background: IL-10 is well known for its ability to block the expression and production of numerous proinflammatory cytokines, in this manner preventing the development of excessive or chronic immune activation. IL-10-induced transcriptional repression of CXCL8 and TNFA genes consists of 2 distinct phases: an early phase, occurring rapidly and in a protein synthesis-independent manner, followed by a second phase that is more delayed and dependent on protein synthesis.Objective: We sought to identify the mechanisms through which IL-10 rapidly and directly suppresses LPS-induced CXCL8 and TNF-alpha transcription, which might be defective under pathologic conditions.Methods: The molecular events triggered by IL-10 in LPS-activated monocytes at the CXCL8 and TNFA loci were investigated by using the chromatin immunoprecipitation assay.Results: Inhibition of LPS-induced CXCL8 and TNF-alpha expression by IL-10 proceeds through a common mechanism targeting LPS-induced phosphorylation of the nuclear factor kappa B p65 serine 276 residue (pS(276)p65). As a result, all the pS(276)p65-dependent events occurring at the CXCL8 and TNFA loci are consistently reduced, ultimately leading to a reduction in transcript elongation. Additionally, IL-10 selectively controls CXCL8 transcript elongation through histone deacetylase (HDAC) 2-dependent covalent chromatin modifications, disrupting the assembly of the transcriptional machinery. Remarkably, PBMCs from patients with acute-phase chronic obstructive pulmonary disease, which express negligible HDAC2 levels, are scarcely affected by IL-10 in terms of inhibition of CXCL8 expression.Conclusions: This study provides mechanistic evidence that IL-10 creates a chromatin environment that decreases the transcriptional rate of CXCL8 and TNF-alpha to Toll-like receptor 4-activating signals. Data identify novel molecular targets for therapeutic strategies aimed at dampening inflammation in pathologies such as chronic obstructive pulmonary disease, in which reduced intracellular HDAC2 levels have been described.