Gene-specific control of inflammation by TLR-induced chromatin modifications
Gene-specific control of inflammation by TLR-induced chromatin modifications
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DOI：
10.1038/nature05836
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发表时间：
2007-06-21
期刊：
影响因子：
64.8
通讯作者：
Medzhitov, Ruslan
中科院分区：
文献类型：
--
作者：
Foster, Simmie L.;Hargreaves, Diana C.;Medzhitov, Ruslan
Toll样受体（TLR）诱导多组分炎症反应，必须严格调节以避免组织损伤。大多数已知的调节机制靶向TLR信号传导途径，从而广泛抑制炎症反应的多个方面。鉴于TLR诱导的基因的功能多样性，我们提出，额外的，基因特异性的调节机制存在，允许个别方面的TLR诱导的反应进行差异调节。使用在小鼠巨噬细胞的脂多糖耐受性的体外系统，我们表明，TLR诱导的基因分为两类的基础上，他们的功能和监管要求。我们证明，代表从两个类获得不同的模式TLR诱导的染色质修饰。这些基因特异性染色质修饰与一类基因（包括促炎介质）的瞬时沉默和第二类基因（包括抗菌效应物）的引发相关。这些发现说明了巨噬细胞的适应性反应，并揭示了炎症的组分特异性调节。
Toll-like receptors (TLRs) induce a multi-component inflammatory response that must be tightly regulated to avoid tissue damage. Most known regulatory mechanisms target TLR signalling pathways and thus broadly inhibit multiple aspects of the inflammatory response. Given the functional diversity of TLR-induced genes, we proposed that additional, gene-specific regulatory mechanisms exist to allow individual aspects of the TLR-induced response to be differentially regulated. Using an in vitro system of lipopolysaccharide tolerance in murine macrophages, we show that TLR-induced genes fall into two categories on the basis of their functions and regulatory requirements. We demonstrate that representatives from the two classes acquire distinct patterns of TLR-induced chromatin modifications. These gene-specific chromatin modifications are associated with transient silencing of one class of genes, which includes pro-inflammatory mediators, and priming of the second class, which includes antimicrobial effectors. These findings illustrate an adaptive response in macrophages and reveal component-specific regulation of inflammation.