Nature:曹雪涛院士发现IL-6免疫调节新机制

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机体以“发炎”的方式抗感染，但有时会过度。究竟哪些蛋白、通过什么方式调控“发炎”程度，既能帮助机体清除病原体又不导致自损？19日，《自然》杂志在线发表了我国科学家在天然免疫与炎症调控机制研究上的新进展，该论文由中国工程院院士、中国医学科学院院长曹雪涛实验室完成。

据介绍，在973计划与国家自然科学基金重点项目的资助下，曹雪涛与中国医学科学院医学分子生物学国家重点实验室博士后张迁及第二军医大学医学免疫学国家重点实验室博士生沈其骢等组成联合研究团队，发现了表观遗传酶Tet2能显著地反馈性抑制炎症因子IL-6的分泌，这一抑制发生在炎症免疫活化晚期；通过急性内毒素休克与结肠炎小鼠模型，证明了Tet2在抑制炎症持续发展中的重要作用；通过质谱等技术，发现Tet2可以结合一种名为HDAC2的表观抑制性调控分子，选择性地直接结合炎症因子IL-6的基因启动子从而阻止其表达。

曹雪涛表示，这一研究是免疫与炎症研究领域的新进展，首次揭示了Tet蛋白参与天然免疫过程和促进炎症消退的作用机理，与目前广泛认为Tet2促进基因转录不同，该工作证明Tet2具有转录负调控作用，即抑制作用，这提示Tet2的生物学作用及其调控机制还有待深入研究。

研究结果为促进炎症消退、抑制炎症持续反应、阻止自身免疫病等提出了新机制，为免疫学与表观遗传学交叉研究提出了新方向。

来源：科技日报

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Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6

Qian Zhang,        Kai Zhao,        Qicong Shen,        Yanmei Han,        Yan Gu,        Xia Li,        Dezhi Zhao,        Yiqi Liu, Chunmei Wang,        Xiang Zhang,        Xiaoping Su,        Juan Liu,        Wei Ge,        Ross L. Levine,        Nan Li        & Xuetao Cao

Epigenetic modifiers have fundamental roles in defining unique cellular identity through the establishment and maintenance of lineage-specific chromatin and methylation status1. Several DNA modifications such as 5-hydroxymethylcytosine (5hmC) are catalysed by the ten eleven translocation (Tet) methylcytosine dioxygenase family members2, and the roles of Tet proteins in regulating chromatin architecture and gene transcription independently of DNA methylation have been gradually uncovered3. However, the regulation of immunity and inflammation by Tet proteins independent of their role in modulating DNA methylation remains largely unknown. Here we show that Tet2 selectively mediates active repression of interleukin-6 (IL-6) transcription during inflammation resolution in innate myeloid cells, including dendritic cells and macrophages. Loss of Tet2 resulted in the upregulation of several inflammatory mediators, including IL-6, at late phase during the response to lipopolysaccharide challenge. Tet2-deficient mice were more susceptible to endotoxin shock and dextran-sulfate-sodium-induced colitis, displaying a more severe inflammatory phenotype and increased IL-6 production compared to wild-type mice. IκBζ, an IL-6-specific transcription factor, mediated specific targeting of Tet2 to the Il6 promoter, further indicating opposite regulatory roles of IκBζ at initial and resolution phases of inflammation. For the repression mechanism, independent of DNA methylation and hydroxymethylation, Tet2 recruited Hdac2 and repressed transcription of Il6 via histone deacetylation. We provide mechanistic evidence for the gene-specific transcription repression activity of Tet2 via histone deacetylation and for the prevention of constant transcription activation at the chromatin level for resolving inflammation.



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