Both Erk and p38 kinases are necessary for cytokine gene transcription
Both Erk and p38 kinases are necessary for cytokine gene transcription
复制标题
DOI：
10.1165/ajrcmb.20.4.3420
复制
发表时间：
1999-04-01
影响因子：
6.4
通讯作者：
Hunninghake, GW
中科院分区：
文献类型：
--
作者：
Carter, AB;Monick, MM;Hunninghake, GW
脓毒症引起的急性肺损伤的一个重要特征是内毒素（LPS）刺激肺泡巨噬细胞（AM）释放细胞因子。还已知LPS激活其他类型细胞中的促分裂原活化蛋白激酶（MAPK）家族的各种成员。在这项研究中，我们评估是否多个成员的MAPK家族调节细胞因子基因的表达在LPS刺激的AM。我们发现，LPS激活细胞外信号调节激酶（Erk）和p38激酶，并且当细胞在血清中培养时，这种激活增强。抑制Erk（PD 98059）或p38（SB 203580）激酶通路导致细胞因子（白细胞介素-6和肿瘤坏死因子）信使RNA积累和细胞因子释放仅部分减少，而同时抑制两种通路导致细胞因子基因表达降低至接近对照水平。核运行的分析表明，这些MAPK途径对LPS诱导的细胞因子基因的表达的影响是归因于，至少部分地，基因转录的调节。这些研究结果表明，Erk和p38激酶途径的激活是必要的最佳细胞因子基因的表达在LPS刺激的人AM，MAPK途径中发挥关键作用的炎症反应，发生在脓毒症诱导的急性肺损伤。
A critical feature of sepsis-induced acute lung injury is the release of cytokines from endotoxin (LPS)stimulated alveolar macrophages (AM). LPS is also known to activate various members of the mitogen-activated protein kinase (MAPK) family in other types of cells. In this study, we evaluated whether multiple members of the MAPK family regulate cytokine gene expression in LPS-stimulated AM. We found that LPS activates both the extracellular signal-regulated kinase (Erk) and p38 kinases, and that this activation is augmented when the cells are cultured in serum. Inhibition of either the Erk (with PD98059) or p38 (with SB203580) kinase pathway resulted in only a partial reduction in cytokine (interleukin-6 and tumor necrosis factor) messenger RNA accumulation and cytokine release, whereas inhibition of both pathways simultaneously resulted in a decrease in cytokine gene expression to near-control levels. Nuclear run-on assays showed that the effect of these MAPK pathways on LPS-induced expression of the cytokine genes was attributable, at least in part, to regulation of gene transcription. These findings suggest that activation of both the Erk and p38 kinase pathways is necessary for optimal cytokine gene expression in LPS-stimulated human AM, and that the MAPK pathways play a critical role in the inflammatory response that occurs in sepsis-induced acute lung injury.