Nrf2 Regulates Anti-Inflammatory A20 Deubiquitinase Induction by LPS in Macrophages in Contextual Manner.
Nrf2 Regulates Anti-Inflammatory A20 Deubiquitinase Induction by LPS in Macrophages in Contextual Manner.
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DOI：
10.3390/antiox10060847
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发表时间：
2021-05-26
期刊：
影响因子：
--
通讯作者：
Reddy SP
中科院分区：
文献类型：
--
作者：
Potteti HR;Venkareddy LK;Noone PM;Ankireddy A;Tamatam CR;Mehta D;Tiruppathi C;Reddy SP
氧化和炎症刺激后炎症基因转录的异常调节可最终导致不受控制的全身炎症导致器官功能障碍。Nrf2转录因子通过上调抗氧化基因表达来抑制细胞应激并控制炎症，而tnf α-诱导蛋白3 （TNFAIP3，又名A20）去泛素酶通过控制NF-kB信号传导来抑制组织炎症。在这里，我们报告了单核细胞/骨髓源性巨噬细胞（MDMΦs）炎症刺激LPS诱导A20需要Nrf2，而肺巨噬细胞（LDMΦs）则不需要Nrf2。lps诱导的A20在Nrf2−/−MDMΦs中的表达显著降低，并且通过补充抗氧化剂无法恢复。Nrf2缺乏显著损害LPS刺激下的A20 mRNA表达Nrf2−/−MDMΦs， ChIP实验显示LPS刺激下Nrf2在启动子Nrf2−/−MDMΦs富集，表明Nrf2直接调控A20的表达。与MDMΦs相反，LPS刺激的A20表达在Nrf2 - / - LDMΦs中并没有受到很大的损害，体外和体内的ChIP分析显示，LPS处理后，LDMΦ中A20启动子上的Nrf2结合没有增加。总的来说，这些结果表明Nrf2在内毒素诱导巨噬细胞A20转录的最佳过程中起着至关重要的作用，并且这种调节是在上下文方式下发生的。
The aberrant regulation of inflammatory gene transcription following oxidant and inflammatory stimuli can culminate in unchecked systemic inflammation leading to organ dysfunction. The Nrf2 transcription factor dampens cellular stress and controls inflammation by upregulating antioxidant gene expression and TNFα-induced Protein 3 (TNFAIP3, aka A20) deubiquitinase by controlling NF-kB signaling dampens tissue inflammation. Here, we report that Nrf2 is required for A20 induction by inflammatory stimuli LPS in monocyte/bone marrow derived macrophages (MDMΦs) but not in lung-macrophages (LDMΦs). LPS-induced A20 expression was significantly lower in Nrf2−/− MDMΦs and was not restored by antioxidant supplementation. Nrf2 deficiency markedly impaired LPS-stimulated A20 mRNA expression Nrf2−/− MDMΦs and ChIP assays showed Nrf2 enrichment at the promoter Nrf2−/− MDMΦs upon LPS stimulation, demonstrating that Nrf2 directly regulates A20 expression. Contrary to MDMΦs, LPS-stimulated A20 expression was not largely impaired in Nrf2−/− LDMΦs ex vivo and in vivo and ChIP assays showed lack of increased Nrf2 binding at the A20 promoter in LDMΦ following LPS treatment. Collectively, these results demonstrate a crucial role for Nrf2 in optimal A20 transcriptional induction in macrophages by endotoxin, and this regulation occurs in a contextual manner.
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DOI：
10.4049/jimmunol.0804248
发表时间：
2009-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Reddy NM;Kleeberger SR;Kensler TW;Yamamoto M;Hassoun PM;Reddy SP
通讯作者：
Reddy SP
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
5.3
作者：
Shin, Soona;Wakabayashi, Nobunao;Kensler, Thomas W.
通讯作者：
Kensler, Thomas W.
DOI：
10.1165/rcmb.2009-0136oc
发表时间：
2011-04-01
影响因子：
6.4
作者：
Aesif, Scott W.;Anathy, Vikas;Janssen-Heininger, Yvonne M. W.
通讯作者：
Janssen-Heininger, Yvonne M. W.
影响因子：
56.9
作者：
Lee, EG;Boone, DL;Ma, A
通讯作者：
Ma, A