The protein kinase PKR is required for p38 MAPK activation and the innate immune response to bacterial endotoxin
The protein kinase PKR is required for p38 MAPK activation and the innate immune response to bacterial endotoxin
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DOI：
10.1093/emboj/19.16.4292
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发表时间：
2000-08-15
期刊：
影响因子：
11.4
通讯作者：
Williams, BRG
中科院分区：
文献类型：
--
作者：
Goh, KC;deVeer, MJ;Williams, BRG
蛋白激酶RNA调节（PKR）是先天性抗病毒免疫的一个既定组成部分。最近，PKR已被证明是必不可少的信号转导在其他情况下的细胞应激。PKR与应激活化蛋白激酶（SAPKs）如p38丝裂原活化蛋白激酶（MAPK）的关系尚不清楚。使用来自PKR野生型和无效小鼠的胚胎成纤维细胞，我们建立了在由双链RNA、脂多糖（LPS）和促炎细胞因子激活SAPK中对PKR的需要。这并不反映在PKR无效背景下激活SAPK的全局失败，因为这些激酶通常由茴香霉素和其他物理化学应激激活。通过用人PKR重建，在永生化PKR缺失细胞中恢复p38 MAPK的激活。我们还表明，LPS诱导的白细胞介素-6和白细胞介素-12 mRNA是有缺陷的PKR-null细胞，这些细胞因子的生产是受损的PKR-null小鼠与LPS的挑战，我们的研究结果表明，第一次，PKR是必需的p38 MAPK信号转导和发挥潜在的重要作用，在先天性反应对细菌内毒素。
Protein kinase RNA-regulated (PKR) is an established component of innate antiviral immunity. Recently, PKR has been shown to be essential for signal transduction in other situations of cellular stress. The relationship between PKR and the stress-activated protein kinases (SAPKs), such as p38 mitogen-activated protein kinase (MAPK), is not clear. Using embryonic fibroblasts from PKR wild-type and null mice, we established a requirement for PKR in the activation of SAPKs by double-stranded RNA, lipopolysaccharide (LPS) and proinflammatory cytokines, This does not reflect a global failure to activate SAPKs in the PKR-null background as these kinases are activated normally by anisomycin and other physicochemical stress. Activation of p38 MAPK was restored in immortalized PKR-null cells by reconstitution with human PKR. We also show that LPS induction of interleukin-6 and interleukin-12 mRNA is defective in PKR-null cells, and that production of these cytokines is impaired in PKR-null mice challenged with LPS, Our findings indicate, for the first time, that PKR is required for p38 MAPK signaling and plays a potentially important role in the innate response against bacterial endotoxin.