p53 Integrates host defense and cell fate during bacterial pneumonia.
p53 Integrates host defense and cell fate during bacterial pneumonia.
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DOI：
10.1084/jem.20121674
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发表时间：
2013-05-06
期刊：
影响因子：
--
通讯作者：
Fessler MB
中科院分区：
文献类型：
--
作者：
Madenspacher JH;Azzam KM;Gowdy KM;Malcolm KC;Nick JA;Dixon D;Aloor JJ;Draper DW;Guardiola JJ;Shatz M;Menendez D;Lowe J;Lu J;Bushel P;Li L;Merrick BA;Resnick MA;Fessler MB
p53 缺失增强了中性粒细胞介导的肺部细菌清除，但以组织稳态为代价，导致死亡率增加。癌症和感染是人类死亡的主要原因，分别源于基因组和宿主对环境因素的防御不足。转录因子p53在人类肿瘤抑制中发挥着核心作用。尽管 p53 在免疫细胞中表达并且对应激源有广泛的反应，但实际上尚不清楚 p53 是否调节宿主对感染的防御。我们报告说，幼稚 p53−/− 小鼠的肺部表现出全基因组诱导富含 NF-κB 反应元件的促炎基因，表明存在 1 型免疫启动。 p53缺失和p53抑制剂治疗的小鼠在肺内感染后比对照组更有效地清除革兰氏阴性和阳性细菌。这至少部分是由大量抗凋亡、TLR 高反应性肺泡巨噬细胞产生的细胞因子引起的，这些细胞因子可增强气道中性粒细胞增多。 p53−/− 中性粒细胞反过来表现出增强的吞噬作用、Nox 依赖性氧化剂生成、脱颗粒和细菌杀灭作用。 p53 抑制可增强小鼠中性粒细胞的细菌杀灭作用和人类中性粒细胞的氧化剂生成作用。尽管细菌清除能力增强，但受感染的 p53−/− 小鼠的死亡率却因肺损伤加重而增加。因此，p53 通过调节杀菌功能和吞噬细胞的命运来调节宿主防御，揭示了环境损伤期间基因组防御和宿主之间的基本联系。
p53 deletion augments neutrophil-mediated bacterial clearance in the lung at the expense of tissue homeostasis, leading to increased mortality. Cancer and infection are predominant causes of human mortality and derive, respectively, from inadequate genomic and host defenses against environmental agents. The transcription factor p53 plays a central role in human tumor suppression. Despite its expression in immune cells and broad responsiveness to stressors, it is virtually unknown whether p53 regulates host defense against infection. We report that the lungs of naive p53−/− mice display genome-wide induction of NF-κB response element–enriched proinflammatory genes, suggestive of type 1 immune priming. p53-null and p53 inhibitor–treated mice clear Gram-negative and -positive bacteria more effectively than controls after intrapulmonary infection. This is caused, at least in part, by cytokines produced by an expanded population of apoptosis-resistant, TLR-hyperresponsive alveolar macrophages that enhance airway neutrophilia. p53−/− neutrophils, in turn, display heightened phagocytosis, Nox-dependent oxidant generation, degranulation, and bacterial killing. p53 inhibition boosts bacterial killing by mouse neutrophils and oxidant generation by human neutrophils. Despite enhanced bacterial clearance, infected p53−/− mice suffer increased mortality associated with aggravated lung injury. p53 thus modulates host defense through regulating microbicidal function and fate of phagocytes, revealing a fundamental link between defense of genome and host during environmental insult.
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DOI：
10.1006/bbrc.1997.6529
发表时间：
1997-04-28
影响因子：
3.1
作者：
Hsieh, SC;Huang, MH;Yu, CL
通讯作者：
Yu, CL
DOI：
10.4161/cc.9.7.11508
发表时间：
2010-04-01
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Leonova KI;Shneyder J;Antoch MP;Toshkov IA;Novototskaya LR;Komarov PG;Komarova EA;Gudkov AV
通讯作者：
Gudkov AV
影响因子：
2.7
作者：
Gungor, Nejla;Haegens, Astrid;van Schooten, Frederik J.
通讯作者：
van Schooten, Frederik J.
影响因子：
4.8
作者：
Ak, Prashanth;Levine, Arnold J.
通讯作者：
Levine, Arnold J.
影响因子：
4.8
作者：
Donato, NJ;Perez, M
通讯作者：
Perez, M