MAP kinase phosphatase 1 controls innate immune responses and suppresses endotoxic shock.
MAP kinase phosphatase 1 controls innate immune responses and suppresses endotoxic shock.
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DOI：
10.1084/jem.20051794
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发表时间：
2006-01-23
期刊：
影响因子：
--
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Zhao Q;Wang X;Nelin LD;Yao Y;Matta R;Manson ME;Baliga RS;Meng X;Smith CV;Bauer JA;Chang CH;Liu Y
感染性休克是发病率和死亡率的主要原因。然而，诱发感染性休克的遗传因素尚未完全了解。促炎细胞因子，特别是肿瘤坏死因子（TNF）-α的过度产生以及由此产生的严重低血压在病理生理过程中起着中心作用。丝裂原活化蛋白（MAP）激酶级联在促炎细胞因子的生物合成中至关重要。MAP激酶磷酸酶（MKP）-1是使MAP激酶去磷酸化的双特异性蛋白磷酸酶家族的原型成员。因此，我们假设Mkp-1基因敲除导致MAP激酶激活延长，细胞因子产生增加，内毒素休克易感性增加。在这里，我们表明，敲除Mkp-1实质上敏感小鼠内毒素休克诱导的脂多糖（LPS）的挑战。我们证明，在LPS的挑战，Mkp-1−/−细胞表现出延长p38和c-Jun NH 2-末端激酶激活以及增强TNF-α和白细胞介素（IL）-6的生产相比，野生型细胞。LPS刺激后，Mkp-1基因敲除小鼠产生的TNF-α、IL-6和IL-10显著高于野生型小鼠。因此，Mkp-1敲除小鼠发生严重的低血压和多器官衰竭，并表现出死亡率显著增加。我们的研究表明，MKP-1是先天免疫反应的关键反馈控制调节剂，在抑制内毒素休克中起着关键作用。
Septic shock is a leading cause of morbidity and mortality. However, genetic factors predisposing to septic shock are not fully understood. Excessive production of proinflammatory cytokines, particularly tumor necrosis factor (TNF)-α, and the resultant severe hypotension play a central role in the pathophysiological process. Mitogen-activated protein (MAP) kinase cascades are crucial in the biosynthesis of proinflammatory cytokines. MAP kinase phosphatase (MKP)-1 is an archetypal member of the dual specificity protein phosphatase family that dephosphorylates MAP kinase. Thus, we hypothesize that knockout of the Mkp-1 gene results in prolonged MAP kinase activation, augmented cytokine production, and increased susceptibility to endotoxic shock. Here, we show that knockout of Mkp-1 substantially sensitizes mice to endotoxic shock induced by lipopolysaccharide (LPS) challenge. We demonstrate that upon LPS challenge, Mkp-1−/− cells exhibit prolonged p38 and c-Jun NH2-terminal kinase activation as well as enhanced TNF-α and interleukin (IL)-6 production compared with wild-type cells. After LPS challenge, Mkp-1 knockout mice produce dramatically more TNF-α, IL-6, and IL-10 than do wild-type mice. Consequently, Mkp-1 knockout mice develop severe hypotension and multiple organ failure, and exhibit a remarkable increase in mortality. Our studies demonstrate that MKP-1 is a pivotal feedback control regulator of the innate immune responses and plays a critical role in suppressing endotoxin shock.
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影响因子：
15.3
作者：
D'Andrea, A;Aste-Amezaga, M;Valiante, N M;Ma, X;Kubin, M;Trinchieri, G
通讯作者：
Trinchieri, G
影响因子：
32.4
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56.9
作者：
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通讯作者：
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影响因子：
56.9
作者：
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通讯作者：
Lapadat, R
影响因子：
4.8
作者：
Ma, W;Lim, W;Kumar, A
通讯作者：
Kumar, A