Increased inflammation, impaired bacterial clearance, and metabolic disruption after gram-negative sepsis in Mkp-1-deficient mice.
Increased inflammation, impaired bacterial clearance, and metabolic disruption after gram-negative sepsis in Mkp-1-deficient mice.
复制标题
DOI：
10.4049/jimmunol.0804343
复制
发表时间：
2009-12-01
期刊：
影响因子：
--
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Frazier WJ;Wang X;Wancket LM;Li XA;Meng X;Nelin LD;Cato AC;Liu Y
MAPKs对TLR配体应答的先天免疫细胞产生TNF-α和IL-6至关重要。MAPK磷酸酶1 （Mkp-1）使p38和JNK失活，消除炎症反应。我们之前已经证明，Mkp-1−/−小鼠在LPS和热杀金黄色葡萄球菌的攻击下表现出炎症细胞因子产生加剧和死亡率增加。然而，Mkp-1在革兰氏阴性菌感染过程中对宿主防御的作用尚不清楚。我们用活大肠杆菌刺激Mkp-1+/+和Mkp-1 - / -小鼠，观察Mkp-1缺乏对动物存活、细菌清除率、代谢活性和细胞因子产生的影响。我们发现，Mkp-1缺乏易导致动物加速死亡，并与TNF-α、IL-6和IL-10的产生更强、细菌负担更重、环氧化酶-2和iNOS表达改变以及能量储存动员的实质性变化有关。同样，敲除Mkp-1也使小鼠对盲肠结扎和穿刺引起的败血症敏感。通过中和Ab或基因缺失抑制IL-10可减轻增加的细菌负担。在大肠杆菌感染后3小时给予抗菌抗生素庆大霉素，可保护Mkp-1+/+小鼠免于感染性休克，但对Mkp-1−/−小鼠没有影响。因此，在革兰氏阴性细菌性脓毒症中，Mkp-1不仅在调节细胞因子的产生中起关键作用，而且还协调先天免疫系统的杀菌活性并控制应激代谢反应。
MAPKs are crucial for TNF-α and IL-6 production by innate immune cells in response to TLR ligands. MAPK phosphatase 1 (Mkp-1) deactivates p38 and JNK, abrogating the inflammatory response. We have previously demonstrated that Mkp-1−/− mice exhibit exacerbated inflammatory cytokine production and increased mortality in response to challenge with LPS and heat-killed Staphylococcus aureus. However, the function of Mkp-1 in host defense during live Gram-negative bacterial infection remains unclear. We challenged Mkp-1+/+ and Mkp-1−/− mice with live Escherichia coli i.v. to examine the effects of Mkp-1 deficiency on animal survival, bacterial clearance, metabolic activity, and cytokine production. We found that Mkp-1 deficiency predisposed animals to accelerated mortality and was associated with more robust production of TNF-α, IL-6 and IL-10, greater bacterial burden, altered cyclooxygenase-2 and iNOS expression, and substantial changes in the mobilization of energy stores. Likewise, knockout of Mkp-1 also sensitized mice to sepsis caused by cecal ligation and puncture. IL-10 inhibition by neutralizing Ab or genetic deletion alleviated increased bacterial burden. Treatment with the bactericidal antibiotic gentamicin, given 3 h after Escherichia coli infection, protected Mkp-1+/+ mice from septic shock but had no effect on Mkp-1−/− mice. Thus, during Gram-negative bacterial sepsis Mkp-1 not only plays a critical role in the regulation of cytokine production but also orchestrates the bactericidal activities of the innate immune system and controls the metabolic response to stress.
登录
查看更多内容
DOI：
10.1084/jem.20051753
发表时间：
2006-01-23
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hammer M;Mages J;Dietrich H;Servatius A;Howells N;Cato AC;Lang R
通讯作者：
Lang R
影响因子：
2.2
作者：
EICHBAUM, EB;HARRIS, HW;RAPP, JH
通讯作者：
RAPP, JH
影响因子：
15.9
作者：
HARRIS, HW;GRUNFELD, C;RAPP, JH
通讯作者：
RAPP, JH
影响因子：
4.8
作者：
FEINGOLD, KR;SERIO, MK;GRUNFELD, C
通讯作者：
GRUNFELD, C
影响因子：
8.8
作者：
Angus, D C;Linde-Zwirble, W T;Pinsky, M R
通讯作者：
Pinsky, M R