Carter A B, Monick M M, Hunninghake G W
University of Iowa College of Medicine and the Iowa City Veterans Administration Medical Center, Iowa City, Iowa, USA.
Am J Respir Cell Mol Biol. 1999 Apr;20(4):751-8. doi: 10.1165/ajrcmb.20.4.3420.
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.
脓毒症诱导的急性肺损伤的一个关键特征是内毒素（LPS）刺激的肺泡巨噬细胞（AM）释放细胞因子。已知LPS还能激活其他类型细胞中的丝裂原活化蛋白激酶（MAPK）家族的多个成员。在本研究中，我们评估了MAPK家族的多个成员是否调节LPS刺激的AM中的细胞因子基因表达。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会增强。抑制Erk（用PD98059）或p38（用SB203580）激酶途径仅导致细胞因子（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部分减少，而同时抑制这两种途径则导致细胞因子基因表达降至接近对照水平。核转录分析表明，这些MAPK途径对LPS诱导的细胞因子基因表达的影响至少部分归因于基因转录的调节。这些发现表明，激活Erk和p38激酶途径对于LPS刺激的人AM中最佳的细胞因子基因表达是必要的，并且MAPK途径在脓毒症诱导的急性肺损伤中发生的炎症反应中起关键作用。
