NF-κB and activator protein 1 response elements and the role of histone modifications in IL-1-β-induced TGF-β1 gene transcription
NF-κB and activator protein 1 response elements and the role of histone modifications in IL-1-β-induced TGF-β1 gene transcription
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DOI：
10.4049/jimmunol.176.1.603
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发表时间：
2006-01-01
影响因子：
4.4
通讯作者：
Adcock, IM
中科院分区：
文献类型：
--
作者：
Lee, KY;Ito, K;Adcock, IM
TGF-β1的异常表达被认为在许多慢性炎症和免疫性肺部疾病的发病机制中发挥重要作用，包括哮喘、慢性阻塞性肺病和肺纤维化。真核生物中的基因激活需要协调使用特定的细胞信号、染色质修饰和染色质重塑。我们研究了普遍存在的炎症转录因子 NF-κ B 和 AP-1 在 TGF-β 1 基因激活和 TGF-β 1 启动子组蛋白乙酰化中的作用。 IL-1β 诱导的 TGF-β1 蛋白分泌和 mRNA 表达被放线菌素 D 阻止，并被 kappa B 激酶 2 抑制剂 AS602868 和 JNK 抑制剂 SP600125 减弱，表明一定程度的转录调节是由 NF-kappa B 和 AP-1 途径介导的。我们证明 IL-1 beta 激活 NF-kappa B 的 p65 亚基和 AP-1 的 c-Jun 亚基。使用染色质免疫沉淀测定，我们观察到 p65 和 c-jun 的连续募集，伴随着组蛋白 H4 和 H3 乙酰化水平的有序升高以及天然 TGF-β 1 启动子中不同区域的 RNA 聚合酶 II 的募集。通过基于 ELISA 的结合测定证实了 TGF-β 1 启动子中的特异性 NF-κ B 和 AP-1 结合位点，组蛋白脱乙酰酶抑制剂曲古抑菌 A 增强基础和 IL-1 β 诱导的 TGF-β 1 mRNA 表达的观察结果支持了 TGF-β 1 诱导中组蛋白过度乙酰化的证据。我们的结果表明，IL-1 β 刺激的 TGF-β 1 转录受到 NF-κ B 和 AP-1 的暂时调节，并涉及不同启动子位点的组蛋白过度乙酰化。
Abnormal expression of TGF-beta 1 is believed to play an important role in the pathogenesis of a number of chronic inflammatory and immune lung diseases, including asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis. Gene activation in eukaryotes requires coordinated use of specific cell signals, chromatin modifications, and chromatin remodeling. We studied the roles of the ubiquitous inflammatory transcription factors, NF-kappa B and AP-1, in activation of the TGF-beta 1 gene and histone aceltylation at the TGF-beta 1 promoter. IL-1 beta-induced TGF-beta 1 protein secretion and mRNA expression were prevented by actinomycin D and were attenuated by the inhibitor of kappa B kinase 2 inhibitor AS602868 and the JNK inhibitor SP600125, suggesting a degree of transcriptional regulation mediated by the NF-kappa B and AP-1 pathways. We demonstrated that IL-1 beta activated the p65 subunit of NF-kappa B and the c-Jun subunit of AP-1. Using chromatin immunoprecipitation assays, we observed a sequential recruitment of p65 and c-jun, accompanying ordered elevation of the levels of histone H4 and H3 acetylation and recruitment of RNA polymerase II at distinct regions in the native TGF-beta 1 promoter. The specific NF-kappa B and AP-1 binding sites in the TGF-beta 1 promoter were confirmed by an ELISA-based binding assay, and evidence for histone hyperacetylation in TGF-beta 1 induction was supported by the observation that the histone deacetylase inhibitor trichostatin A enhanced basal and IL-1 beta-induced TGF-beta 1 mRNA expression. Our results suggest that IL-1 beta-stimulated transcription of TGF-beta 1 is temporally regulated by NF-kappa B and AP-1 and involves histone hyperacetylation at distinct promoter sites.