Triptolide inhibits IL-12/IL-23 expression in APCs via CCAAT/enhancer-binding protein alpha.
Triptolide inhibits IL-12/IL-23 expression in APCs via CCAAT/enhancer-binding protein alpha.
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DOI：
10.4049/jimmunol.0903417
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发表时间：
2010-04-01
期刊：
影响因子：
--
通讯作者：
Ma X
中科院分区：
文献类型：
--
作者：
Zhang Y;Ma X
雷公藤甲素是一种从中草药植物雷公藤中纯化出来的生物活性成分，在东亚地区广泛用于治疗系统性红斑狼疮、类风湿关节炎、肾炎、bechet病、牛皮癣、特应性皮炎和哮喘。然而，其免疫学机制尚不清楚。IL-12和IL-23是密切相关的异二聚体细胞因子，具有共同的亚基p40。它们由apc产生，分别是Th1和Th17细胞产生和发挥作用的关键因子。它们与几种自身免疫性疾病的发病机制密切相关。在这项研究中，我们研究了雷公藤甲素抑制APCs中p40基因表达的分子机制。我们证明雷公藤甲素在转录水平上的作用部分是通过靶向CCAAT/增强子结合蛋白-α (C/EBPα)，后者直接与p40启动子相互作用并抑制其在炎症巨噬细胞中的转录。雷公藤甲素可以激活C/EBPα的转录，而Ser21和Thr222/226的磷酸化对C/EBPα抑制p40至关重要。此外，雷公藤甲素对C/EBPα的激活依赖于上游激酶ERK1/2和Akt-GSK3β。这项研究为雷公藤甲素的免疫调节能力提供了机制见解，并对其在自身免疫性疾病中的治疗应用具有重要意义。
Triptolide is a biologically active component purified from Chinese herbal plant Tripterygium wilfordii Hook F. It is widely used in East Asia for treatment of systemic lupus erythematosus, rheumatoid arthritis, nephritis, Bechect’s disease, psoriasis, atopic dermatitis, and asthma. However, its immunological mechanisms are poorly understood. IL-12 and IL-23 are closely related heterodimeric cytokines that share the common subunit p40. They are produced by APCs and are key factors in the generation and effector functions of Th1 and Th17 cells, respectively. They have been strongly implicated in the pathogenesis of several autoimmune disorders. In this study, we investigated the molecular mechanism whereby triptolide inhibits the expression of the p40 gene in APCs. We demonstrate that triptolide does so at the transcriptional level in part through targeting CCAAT/enhancer-binding protein-α (C/EBPα), which directly interacts with the p40 promoter and inhibits its transcription in inflammatory macrophages. Triptolide can activate the transcription of C/EBPα, and phosphorylation of Ser21 and Thr222/226 critical for C/EBPα inhibition of p40. Further, activation of C/EBPα by triptolide is dependent on upstream kinases ERK1/2 and Akt-GSK3β. This study provides mechanistic insights into the immunomodulatory capacity of triptolide and has strong implications for its therapeutic applications in autoimmune diseases.
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