The role of p38 mitogen-activated kinase (MAPK) in the mechanism regulating cyclooxygenase gene expression in equine leukocytes
The role of p38 mitogen-activated kinase (MAPK) in the mechanism regulating cyclooxygenase gene expression in equine leukocytes
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DOI：
10.1016/j.vetimm.2007.06.001
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发表时间：
2007-08-15
影响因子：
1.8
通讯作者：
Jones, Samuel L.
中科院分区：
文献类型：
--
作者：
Eckert, Rachael E.;Neuder, Laura E.;Jones, Samuel L.
本研究的目的是明确p38丝裂原活化激酶（MAPK）在调节脂多糖（LPS）激活的马白细胞中促炎性环氧合酶（考克斯）基因表达的信号传导机制中的作用，以确定内毒素血症马抗炎治疗的新靶点。已显示p38 MAPK正调节人白细胞中的炎性基因表达，并且可被多种刺激物（包括LPS、TNF-α和IL-1）激活。激活相关的磷酸化p38 MAPK与几种炎症基因的上调有关，包括考克斯-2，其最终导致产生前列腺素类，前列腺素类负责与内毒素血症相关的病理生理学。我们的假设是，p38 MAPK的激活是必要的LPS诱导考克斯-2在马外周血白细胞的表达。我们通过研究特异性p38 MAPK抑制剂SB 203580和SB 202190对LPS诱导的马白细胞考克斯-2蛋白表达和PGE（2）产生的影响来验证我们的假设。LPS刺激激活p38 MAPK和增加考克斯-2表达的剂量依赖性的方式，观察到最大激活后30分钟和4小时，分别在10 ng/ml的LPS浓度。相反，LPS刺激不影响考克斯-1蛋白表达。SB 203580或SB 202190预处理显著抑制LPS诱导的激活相关的p38 MAPK磷酸化、考克斯-2 mRNA和蛋白水平以及马白细胞中PGE 2的产生。在10 μ M SB 203580的浓度下实现了对LPS诱导的考克斯-2蛋白表达的最大抑制。我们的结论是，p38 MAPK是必不可少的LPS诱导的考克斯-2的表达表明，p38 MAPK是一个潜在的目标，在马的内毒素血症的抗炎治疗。(c)2007 Elsevier B. V.保留所有权利。
The goal of this study was to define the role for p38 mitogen-activated kinase (MAPK) in the signaling mechanism regulating pro-inflammatory cyclooxygenase (COX) gene expression in lipopolysaccharide (LPS)-activated equine leukocytes for the purposes of identifying novel targets for anti-inflammatory therapy in endotoxemic horses. The p38 MAPK has been shown to positively regulate inflammatory gene expression in human leukocytes and can be activated by a variety of stimuli including LPS, TNF-alpha, and IL-1. Activation-associated phosphorylated p38 MAPK has been implicated in the up-regulation of several inflammatory genes, including COX-2 which ultimately results in the production of prostanoids that are responsible for the pathophysiology associated with endotoxemia. Our hypothesis is that activation of p38 MAPK is essential for LPS-induced COX-2 expression in equine peripheral blood leukocytes. We tested our hypothesis by investigating the effects of the specific p38 MAPK inhibitors SB203580 and SB202190 on LPS-induced COX-2 protein expression and PGE(2) production in equine leukocytes. LPS stimulation activated p38 MAPK and increased COX-2 expression in a dose-dependent manner with maximal activation observed after 30 min and 4 h, respectively, at a concentration of 10 ng/ml LPS. In contrast, LPS stimulation did not affect COX-1 protein expression. Pretreatment with SB203580 or SB202190 significantly inhibited LPS-induced activation-associated p38 MAPK phosphorylation, COX-2 mRNA and protein levels, and PGE2 production in equine leukocytes. Maximal inhibition of LPS-induced COX-2 protein expression was achieved at a concentration of 10 mu M SB203580. We concluded that p38 MAPK is essential for LPS-induced COX-2 expression suggesting that p38 MAPK is a potential target for anti-inflammatory therapy during equine endotoxemia. (c) 2007 Elsevier B.V. All rights reserved.