The inflammatory response to double stranded DNA in endothelial cells is mediated by NFκB and TNFα.
The inflammatory response to double stranded DNA in endothelial cells is mediated by NFκB and TNFα.
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DOI：
10.1371/journal.pone.0019910
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Yarmush ML
中科院分区：
文献类型：
--
作者：
Patel SJ;Jindal R;King KR;Tilles AW;Yarmush ML
内皮细胞是血管内和血管外组织之间的重要屏障，是先天免疫和炎症过程中危险信号的关键感受器、通信者和放大器。双链DNA(DsDNA)在损伤过程中从受损的宿主细胞中释放出来，或在感染过程中被病原体引入，已成为一个强有力的危险信号。虽然dsDNA介导的免疫应答在免疫细胞中得到了广泛的研究，但对dsDNA对血管内皮细胞的直接和间接影响知之甚少。在这项研究中，我们发现直接dsDNA刺激内皮细胞可以诱导强烈的促炎反应，表现为ICAM1、E-选择素和VCAM1的表达增加，并增强了白细胞的粘附性。这种反应依赖于应激激酶JNK和p38MAPK，需要促炎转录因子NFκB和IRF3的激活，并触发强烈的肿瘤坏死因子α的分泌，以维持内皮的二次激活。DNA诱导的肿瘤坏死因子α的分泌在体内被证明是必不可少的，因为肿瘤坏死因子受体缺陷的小鼠不能对双链DNA产生急性炎症反应。我们的发现表明，内皮细胞在介导dsDNA诱导的炎症反应中起着积极的作用，并暗示其在建立对无菌损伤或全身感染的急性炎症反应中的重要性，在这些情况下，宿主或病原体衍生的dsDNA可能作为危险信号。
Endothelial cells represent an important barrier between the intravascular compartment and extravascular tissues, and therefore serve as key sensors, communicators, and amplifiers of danger signals in innate immunity and inflammation. Double stranded DNA (dsDNA) released from damaged host cells during injury or introduced by pathogens during infection, has emerged as a potent danger signal. While the dsDNA-mediated immune response has been extensively studied in immune cells, little is known about the direct and indirect effects of dsDNA on the vascular endothelium. In this study we show that direct dsDNA stimulation of endothelial cells induces a potent proinflammatory response as demonstrated by increased expression of ICAM1, E-selectin and VCAM1, and enhanced leukocyte adhesion. This response was dependent on the stress kinases JNK and p38 MAPK, required the activation of proinflammatory transcription factors NFκB and IRF3, and triggered the robust secretion of TNFα for sustained secondary activation of the endothelium. DNA-induced TNFα secretion proved to be essential in vivo, as mice deficient in the TNF receptor were unable to mount an acute inflammatory response to dsDNA. Our findings suggest that the endothelium plays an active role in mediating dsDNA-induced inflammatory responses, and implicate its importance in establishing an acute inflammatory response to sterile injury or systemic infection, where host or pathogen derived dsDNA may serve as a danger signal.
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DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
Bennett, BL;Sasaki, DT;Anderson, DW
通讯作者：
Anderson, DW
影响因子：
15.3
作者：
SCHRECK, R;MEIER, B;MANNEL, DN;DROGE, W;BAEUERLE, PA
通讯作者：
BAEUERLE, PA
DOI：
10.1084/jem.20051654
发表时间：
2005-11-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Okabe Y;Kawane K;Akira S;Taniguchi T;Nagata S
通讯作者：
Nagata S
DOI：
10.1073/pnas.1003738107
发表时间：
2010-05-25
影响因子：
11.1
作者：
Jones, Jonathan W.;Kayagaki, Nobuhiko;Monack, Denise M.
通讯作者：
Monack, Denise M.
影响因子：
64.8
作者：
Hemmi, H;Takeuchi, O;Akira, S
通讯作者：
Akira, S