p38 mitogen-activated protein kinase up-regulates LPS-induced NF-κB activation in the development of lung injury and RAW 264.7 macrophages
p38 mitogen-activated protein kinase up-regulates LPS-induced NF-κB activation in the development of lung injury and RAW 264.7 macrophages
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DOI：
10.1016/j.tox.2006.04.053
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发表时间：
2006-08-01
期刊：
影响因子：
4.5
通讯作者：
Kang, Jihee Lee
中科院分区：
文献类型：
--
作者：
Kim, Hee J.;Lee, Hui S.;Kang, Jihee Lee
阐明在细胞和病理条件下导致核因子-κ B（NF-κ B）的关键调控步骤是非常重要的。p38丝裂原活化蛋白激酶（MAPK）在NF-κ B B活化上游的作用仍有争议。为了使用体内肺损伤模型SB 203580来检查该问题，在脂多糖（LPS）处理（肠内）之前1小时经口给予p38 MAPK抑制剂。LPS处理后4 h处死小鼠。SB 203580显著抑制LPS诱导的p38 MAPK磷酸化、中性粒细胞募集、支气管肺泡灌洗液中总蛋白含量和支气管肺泡细胞凋亡的升高。此外，SB 203580通过下调丝氨酸磷酸化、I κ B-α的降解以及随后NF-κ B的p65亚基向细胞核的移位来阻断LPS诱导的肺组织中NF-κ B活化。很可能，在培养的RAW 264.7巨噬细胞中，SB 203580也以剂量依赖性方式阻断LPS诱导的NF-κ B活化。SB 203580抑制LPS诱导的丝氨酸磷酸化、I κ B-α降解和p65 NF-κ B酪氨酸磷酸化。这些数据表明，p38 MAPK在急性肺损伤期间通过调节I κ B-α和p65 NF-κ B的磷酸化作用于LPS诱导的NF-κ B B活化的上游。由于LPS刺激的巨噬细胞可能导致炎性肺损伤，因此抑制p38 MAPK介导的导致NF-κ B活化的细胞内信号传导途径代表了减轻肺部炎症和实质损伤的靶点。(c)2006爱思唯尔爱尔兰有限公司保留所有权利。
Clarification of the key regulatory steps that lead to nuclear factor-kappa B (NF-kappa B) under cellular and pathological conditions is very important. The action of p38 mitogen-activated protein kinase (MAPK) on the upstream of NF-kappa B activation remains controversial. To examine this issue using an in vivo lung injury model, SB203580, a p38 MAPK inhibitor was given intraorally 1 h prior to lipopolysaccharide (LPS) treatment (intratracheally). The mice were sacrificed 4 h after LPS treatment. SB203580 substantially suppressed LPS-induced rises in p38 MAPK phosphorylation, neutrophil recruitment, total protein content in bronchoalveolar lavage fluid, and apoptosis of bronchoalveolar cells. Furthermore, SB203580 blocked LPS-induced NF-kappa B activation in lung tissue through down-regulation of serine phosphorylation, degradation of I kappa B-alpha, and consequent translocation of the p65 subunit of NF-kappa B to the nucleus. It is likely that, in cultured RAW 264.7 macrophages, SB203580 also blocked LPS-induced NF-kappa B activation in a dose-dependent manner. SB203580 inhibited LPS-induced serine phosphorylation, degradation of I kappa B-alpha, and tyrosine phosphorylation of p65 NF-kappa B. These data indicate that p38 MAPK acts upstream of LPS-induced NF-kappa B activation by modulating the phosphorylation of I kappa B-alpha and p65 NF-kappa B during acute lung injury. Because LPS-stimulated macrophages may contribute to inflammatory lung injury, the inhibition of the p38 MAPK-mediated intracellular signaling pathway leading to NF-kappa B activation represents a target for the attenuation of lung inflammation and parenchymal damage. (c) 2006 Elsevier Ireland Ltd. All rights reserved.