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首页> 外文期刊>Molecular and Cellular Biology >NF-κB1 Inhibits NOD2-Induced Cytokine Secretion through ATF3-Dependent Mechanisms
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NF-κB1 Inhibits NOD2-Induced Cytokine Secretion through ATF3-Dependent Mechanisms

机译：NF-κB1通过ATF3依赖性机制抑制NOD2诱导的细胞因子分泌

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Regulation of microbially induced cytokine secretion is critical in intestinal immune homeostasis. NOD2, the Crohn's disease-associated bacterial peptidoglycan sensor, activates the NF-κB pathway. After chronic NOD2 stimulation in human macrophages, cytokine secretion is significantly attenuated, similar to the situation in the intestinal environment. We find that NF-κB1 (p105/p50) expression is upregulated with chronic NOD2 stimulation and is required for attenuation of cytokine secretion in vitro in human macrophages and in vivo in mice. Upon chronic NOD2 stimulation, regulation of both activating (H3K4Me2 and H4Ac) and inhibitory (H3K27Me3) histone modifications was observed within cytokine gene promoters; these outcomes were NF-κB1 dependent. In addition to enhanced binding to cytokine gene promoters with chronic NOD2 stimulation, NF-κB1 bound to the promoter of the transcriptional repressor, ATF3. ATF3 was then induced and bound to cytokine gene promoters; both features were impaired upon NF-κB1 knockdown. Restoring ATF3 expression under NF-κB1 knockdown conditions restored NOD2-mediated cytokine downregulation. Finally, NF-κB1 and ATF3 cooperate with other inhibitory pathways, including IRAKM and secreted mediators, to downregulate cytokine secretion after chronic NOD2 stimulation. Therefore, we identify NF-κB1 and ATF3 as critical mechanisms through which NOD2 downregulates cytokines and contributes to intestinal immune homeostasis.
机译：微生物诱导的细胞因子分泌的调节在肠道免疫稳态中至关重要。克罗恩氏病相关细菌肽聚糖传感器NOD2激活NF-κB途径。在人类巨噬细胞中慢性NOD2刺激后，细胞因子的分泌显着减弱，类似于肠道环境中的情况。我们发现，NF-κB1（p105 / p50）的表达在慢性NOD2刺激下被上调，并且是减弱人类巨噬细胞中的细胞因子分泌和小鼠体内的细胞因子分泌所必需的。 。在长期的NOD2刺激下，在细胞因子基因启动子中观察到了活化（H3K4Me2和H4Ac）和抑制性（H3K27Me3）组蛋白修饰的调控。这些结果是NF-κB1依赖性的。除了通过慢性NOD2刺激增强与细胞因子基因启动子的结合外，NF-κB1还与转录阻遏物ATF3的启动子结合。然后诱导ATF3并与细胞因子基因启动子结合。 NF-κB1敲低会削弱这两个功能。在NF-κB1敲低条件下恢复ATF3表达可恢复NOD2介导的细胞因子下调。最后，NF-κB1和ATF3与其他抑制途径（包括IRAKM和分泌的介体）协同作用，在慢性NOD2刺激后下调细胞因子的分泌。因此，我们确定NF-κB1和ATF3是NOD2下调细胞因子并促进肠道免疫稳态的关键机制。

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