Gfi1 and Zc3h12c orchestrate a negative feedback loop that inhibits NF-kB activation during inflammation in macrophages
Gfi1 and Zc3h12c orchestrate a negative feedback loop that inhibits NF-kB activation during inflammation in macrophages
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Gfi1 和 Zc3h12c 协调负反馈回路，抑制巨噬细胞炎症期间 NF-kB 的激活
DOI：
10.1016/j.molimm.2020.10.023
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发表时间：
2020-12-01
影响因子：
3.6
通讯作者：
Zheng, Qianqian
中科院分区：
文献类型：
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作者：
Guo, Guo;Fu, Rui;Zheng, Qianqian
NF-kappa B的激活在介导促炎细胞因子的诱导中是必不可少的，并且通过复杂的机制在调节炎症反应中起着关键作用。在这项研究中，Gfi1的缺失被发现与NF-kappa B激活相关的转录组谱相关，包括促炎细胞因子的增加。巨噬细胞中IKK/NF-kappa B信号通路的基因失活表明，Gfi1缺乏导致促炎细胞因子的产生，需要NF-kappa B的激活。更重要的是，我们揭示了一种尚未被研究的机制，包括Gfi1和Zc3h12c，对NF-kappa B的激活起到负调控作用。Gfi1和Zc3h12c均可抑制NF-kappa B的活化，双敲除Gfi1和Zc3h12c在抑制促炎细胞因子产生中具有叠加作用。Gfi1缺失可上调Zc3h12c，进而抑制NF-kappa B的激活。因此，本研究描述了Zc3h12c在巨噬细胞炎症过程中通过NF-kappa B激活增强Gfi1负调控的功能。
NF-kappa B activation is essential in mediating the induction of pro-inflammatory cytokines and also plays a key role in regulating the inflammatory response through intricate mechanisms. In this study, loss of Gfi1 was found to be associated with transcriptomic profiles related to NF-kappa B activation, including an increase in pro-inflammatory cytokines. Genetically inactivating the IKK/NF-kappa B signaling pathway in macrophages showed that Gfi1 deficiency led to pro-inflammatory cytokine production requiring NF-kappa B activation. More importantly, we revealed that one of the under-researched mechanisms, involving Gfi1 and Zc3h12c exerted negative regulation on NF-kappa B activation. Both Gfi1 and Zc3h12c were found to inhibit NF-kappa B activation, and double knockout exhibited additive roles of Gfi1 and Zc3h12c in preventing proinflammatory cytokine production. The loss of Gfi1 upregulated Zc3h12c which in turn inhibited NF-kappa B activation. Therefore, this study delineates the function of Zc3h12c in enhancing the negative regulation of Gfi1 through NF-kappa B activation during inflammation in macrophages.