The H3K9 methyltransferase Setdb1 regulates TLR4-mediated inflammatory responses in macrophages.
The H3K9 methyltransferase Setdb1 regulates TLR4-mediated inflammatory responses in macrophages.
复制标题
H3K9甲基转移酶SETDB1调节巨噬细胞中TLR4介导的炎症反应。
DOI：
10.1038/srep28845
复制
发表时间：
2016-06-28
影响因子：
4.6
通讯作者：
Ogawa Y
中科院分区：
文献类型：
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作者：
Hachiya R;Shiihashi T;Shirakawa I;Iwasaki Y;Matsumura Y;Oishi Y;Nakayama Y;Miyamoto Y;Manabe I;Ochi K;Tanaka M;Goda N;Sakai J;Suganami T;Ogawa Y
巨噬细胞促炎细胞因子的产生涉及多种调节机制，受环境和内在应激的影响。特别是，越来越多的证据表明，巨噬细胞分化和功能的表观遗传控制主要在体外。SET结构域，分叉1 （Setdb1，也称为Eset）是一种组蛋白3赖氨酸9 （H3K9）特异性甲基转移酶，对胚胎的早期发育至关重要。在这里，我们证明了巨噬细胞中的Setdb1通过其甲基转移酶活性有效地抑制toll样受体4 （TLR4）介导的促炎细胞因子包括白细胞介素-6的表达。setdb1缺失的分子机制是降低H3K9基础甲基化水平，增加tlr4介导的NF-κB在白细胞介素-6近端启动子区域的募集，从而加速白细胞介素-6启动子活性。此外，巨噬细胞特异性setdb1敲除小鼠在脂多糖攻击下表现出更高的血清白细胞介素-6浓度，并且比野生型小鼠更容易受到内毒素休克。本研究证明H3K9甲基转移酶Setdb1是巨噬细胞体内外促炎细胞因子表达的一种新的表观遗传调控因子。我们的数据将有助于更好地理解免疫系统对各种情况的反应。
Proinflammatory cytokine production in macrophages involves multiple regulatory mechanisms, which are affected by environmental and intrinsic stress. In particular, accumulating evidence has suggested epigenetic control of macrophage differentiation and function mainly in vitro. SET domain, bifurcated 1 (Setdb1, also known as Eset) is a histone 3 lysine 9 (H3K9)-specific methyltransferase and is essential for early development of embryos. Here we demonstrate that Setdb1 in macrophages potently suppresses Toll-like receptor 4 (TLR4)-mediated expression of proinflammatory cytokines including interleukin-6 through its methyltransferase activity. As a molecular mechanism, Setdb1-deficiency decreases the basal H3K9 methylation levels and augments TLR4-mediated NF-κB recruitment on the proximal promoter region of interleukin-6, thereby accelerating interleukin-6 promoter activity. Moreover, macrophage-specific Setdb1-knockout mice exhibit higher serum interleukin-6 concentrations in response to lipopolysaccharide challenge and are more susceptible to endotoxin shock than wildtype mice. This study provides evidence that the H3K9 methyltransferase Setdb1 is a novel epigenetic regulator of proinflammatory cytokine expression in macrophages in vitro and in vivo. Our data will shed insight into the better understanding of how the immune system reacts to a variety of conditions.