Intrapulmonary administration of purified NEIL2 abrogates NF-κB-mediated inflammation.
Intrapulmonary administration of purified NEIL2 abrogates NF-κB-mediated inflammation.
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DOI：
10.1016/j.jbc.2021.100723
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Hazra TK
中科院分区：
文献类型：
--
作者：
Tapryal N;Shahabi S;Chakraborty A;Hosoki K;Wakamiya M;Sarkar G;Sharma G;Cardenas VJ;Boldogh I;Sur S;Ghosh G;Hazra TK
核因子κ B（NF-κB）的异常或组成性激活通过上调参与细胞增殖、存活、血管生成、炎症和转移的基因而导致各种人类炎性疾病和恶性肿瘤。因此，NF-κB信号传导的抑制具有在癌症和炎性疾病中的治疗应用的潜力。Nei样DNA糖基化酶2（Nei-like DNA glycosylase 2，NEIL 2）是一种哺乳动物DNA糖基化酶，通过转录偶联的碱基切除修复途径参与转录活性序列中氧化DNA碱基的优先修复。我们进一步表明，Neil 2基因敲除小鼠对肿瘤坏死因子α（TNFα）和脂多糖诱导的炎症高度敏感。TNFα和脂多糖都是NF-κB的有效激活剂。然而，NEIL 2在NF-κ B介导的炎症中的作用的潜在机制仍不清楚。在这里，我们已经证明了NEIL 2的非经典功能，并证明了与炎症和免疫细胞迁移相关的基因，如Cxcl 1，Cxcl 2，Cxcl 10，Il 6和Tnfα的表达在模拟和TNFα治疗的Neil 2-null小鼠中均显著高于WT小鼠。NEIL 2通过与RelA的Rel同源区直接相互作用阻断NF-κB与靶基因启动子的结合，并通过免疫共沉淀、染色质免疫沉淀和电泳迁移率改变测定抑制促炎基因表达。值得注意的是，通过非侵入性鼻途径肺内给予纯化的NEIL 2显着消除了NF-κB与同源DNA的结合，导致Neil 2缺失小鼠和WT小鼠肺中促炎基因的表达和中性粒细胞募集减少。因此，我们的研究结果突出了NEIL 2作为炎症相关人类疾病生物制剂的潜力。
Aberrant or constitutive activation of nuclear factor kappa B (NF-κB) contributes to various human inflammatory diseases and malignancies via the upregulation of genes involved in cell proliferation, survival, angiogenesis, inflammation, and metastasis. Thus, inhibition of NF-κB signaling has potential for therapeutic applications in cancer and inflammatory diseases. We reported previously that Nei-like DNA glycosylase 2 (NEIL2), a mammalian DNA glycosylase, is involved in the preferential repair of oxidized DNA bases from the transcriptionally active sequences via the transcription-coupled base excision repair pathway. We have further shown that Neil2-null mice are highly sensitive to tumor necrosis factor α (TNFα)- and lipopolysaccharide-induced inflammation. Both TNFα and lipopolysaccharide are potent activators of NF-κB. However, the underlying mechanism of NEIL2's role in the NF-κB–mediated inflammation remains elusive. Here, we have documented a noncanonical function of NEIL2 and demonstrated that the expression of genes, such as Cxcl1, Cxcl2, Cxcl10, Il6, and Tnfα, involved in inflammation and immune cell migration was significantly higher in both mock- and TNFα-treated Neil2-null mice compared with that in the WT mice. NEIL2 blocks NF-κB's binding to target gene promoters by directly interacting with the Rel homology region of RelA and represses proinflammatory gene expression as determined by co-immunoprecipitation, chromatin immunoprecipitation, and electrophoretic mobility-shift assays. Remarkably, intrapulmonary administration of purified NEIL2 via a noninvasive nasal route significantly abrogated binding of NF-κB to cognate DNA, leading to decreased expression of proinflammatory genes and neutrophil recruitment in Neil2-null as well as WT mouse lungs. Our findings thus highlight the potential of NEIL2 as a biologic for inflammation-associated human diseases.
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DOI：
10.1042/bj20121425
发表时间：
2013-12-01
期刊：
The Biochemical journal
影响因子：
--
作者：
D'Cruz AA;Kershaw NJ;Chiang JJ;Wang MK;Nicola NA;Babon JJ;Gack MU;Nicholson SE
通讯作者：
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影响因子：
3.4
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Sardiello M;Cairo S;Fontanella B;Ballabio A;Meroni G
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Meroni G
DOI：
10.1038/nri2413
发表时间：
2008-11
期刊：
Nature reviews. Immunology
影响因子：
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作者：
Ozato K;Shin DM;Chang TH;Morse HC 3rd
通讯作者：
Morse HC 3rd
影响因子：
4.8
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Skurat, AV;Dietrich, AD;Roach, PJ
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Roach, PJ
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16
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Kato K;Ahmad S;Zhu Z;Young JM;Mu X;Park S;Malik HS;Hur S
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