Endothelial cells require STAT3 for protection against endotoxin-induced inflammation.
Endothelial cells require STAT3 for protection against endotoxin-induced inflammation.
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DOI：
10.1084/jem.20030077
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发表时间：
2003-11-17
期刊：
影响因子：
--
通讯作者：
Fu XY
中科院分区：
文献类型：
--
作者：
Kano A;Wolfgang MJ;Gao Q;Jacoby J;Chai GX;Hansen W;Iwamoto Y;Pober JS;Flavell RA;Fu XY
内皮细胞(ECs)被认为是内毒素休克保护作用的重要组成部分。然而，细胞和分子机制还没有很好地确定。在此，我们报道信号转导和转录激活因子(STAT)3是ECs在系统免疫中抗炎功能的重要调节因子。由于STAT3缺乏会导致早期胚胎死亡，我们产生了内皮中STAT3条件性缺失的小鼠(STAT3E−/−)。STAT3E−/−小鼠是健康和有生育能力的，并且分离的内皮细胞在体外启动正常的管状形成。条件性血管内皮细胞而非器官特异性(即肝细胞或心肌细胞)STAT3基因敲除小鼠在内毒素攻击后表现出更高的致死性。STAT3E−/−小鼠的内毒素反应表现为多器官炎症和白细胞浸润，并伴有血清丙氨酸氨基转移酶和天冬氨酸氨基转移酶活性升高，提示器官损伤。随之而来的是，促炎细胞因子的产生被夸大了，并持续了很长一段时间。这一缺陷不能用缺乏抗炎细胞因子来解释，如白介素10和转化生长因子β。相反，我们已经证明了来源于内皮并依赖于STAT3的可溶性活性对于抑制干扰素γ是关键的。这些数据将内皮细胞内的STAT3信号定义为关键的抗炎介质，并为内皮细胞在炎症中的保护功能提供了新的见解。
Endothelial cells (ECs) are believed to be an important component in the protection from lipopolysaccharide (LPS)-induced endotoxic shock. However, the cellular and molecular mechanism is not well defined. Here, we report that signal transducer and activator of transcription (STAT) 3 is an essential regulator of the antiinflammatory function of ECs in systemic immunity. Because STAT3 deficiency results in early embryonic lethality, we have generated mice with a conditional STAT3 deletion in endothelium (STAT3E−/−). STAT3E−/− mice are healthy and fertile, and isolated ECs initiate normal tube formation in vitro. Conditional endothelial but not organ-specific (i.e., hepatocyte or cardiomyocyte) STAT3 knockout mice show an increased susceptibility to lethality after LPS challenge. The LPS response in STAT3E−/− mice shows exaggerated inflammation and leukocyte infiltration in multiple organs combined with elevated activity of serum alanine aminotransferase and aspartate aminotransferase, indicating organ damage. Concomitantly, proinflammatory cytokines are produced at an exaggerated level and for a prolonged period. This defect cannot be explained by lack of antiinflammatory cytokines, such as interleukin 10 and transforming growth factor β. Instead, we have shown that a soluble activity derived from endothelia and dependent on STAT3 is critical for suppression of interferon γ. These data define STAT3 signaling within endothelia as a critical antiinflammatory mediator and provide new insight to the protective function of ECs in inflammation.
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影响因子：
64.5
作者：
Yoo, JY;Huso, DL;Desiderio, S
通讯作者：
Desiderio, S
影响因子：
4.8
作者：
Jacobs, AT;Ignarro, LJ
通讯作者：
Ignarro, LJ
影响因子：
11.4
作者：
Sano, S;Itami, S;Takeda, J
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影响因子：
32.4
作者：
Takeda, K;Clausen, BE;Akira, S
通讯作者：
Akira, S
DOI：
10.1073/pnas.122236099
发表时间：
2002-06-11
影响因子：
11.1
作者：
Costa-Pereira, AP;Tininini, S;Poli, V
通讯作者：
Poli, V