Trametinib, a novel MEK kinase inhibitor, suppresses lipopolysaccharide-induced tumor necrosis factor (TNF)-α production and endotoxin shock
Trametinib, a novel MEK kinase inhibitor, suppresses lipopolysaccharide-induced tumor necrosis factor (TNF)-α production and endotoxin shock
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DOI：
10.1016/j.bbrc.2015.01.160
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发表时间：
2015-03-13
影响因子：
3.1
通讯作者：
Tong Chao-yang
中科院分区：
文献类型：
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作者：
Du Shi-lin;Xue Yuan;Tong Chao-yang
脂多糖（LPS）是最突出的病原体相关分子模式（PAMP）之一，其激活巨噬细胞，引起毒性细胞因子（即肿瘤坏死因子（TNF）-α）的释放，其可引起炎症和内毒素休克。在这里，我们测试了曲美替尼（一种新型高效MAPK/ERK激酶（MEK）抑制剂）对LPS诱导的单核细胞TNF-α反应的潜在作用，并分析了其潜在机制。我们发现，曲美替尼，在nM浓度，显着抑制转化（RAW 264.7细胞）和原代小鼠巨噬细胞中LPS诱导的TNF-α mRNA表达和蛋白分泌。在离体培养的人外周血单核细胞（PBMC）中，这种MEK抑制剂类似地抑制LPS产生INF-α。对于机制研究，我们发现曲美替尼阻断LPS诱导的上述单核细胞中MEK-ERK活化，这解释了缺陷的TNF-α反应。用传统MEK抑制剂PD 98059处理或用MEK 1/2-shRNA慢病毒感染的巨噬细胞或PBMC表现出与曲美替尼相似的缺陷，并使曲美替尼的活性无效。另一方面，在曲美替尼存在下，引入组成型活性（CA）ERK 1恢复了LPS产生的TNF-α。在体内，给予曲美替尼的小鼠在LPS刺激后产生低水平的TNF-α，并且这些小鼠被保护免受LPS诱导的内毒素休克。总之，这些结果表明曲美替尼可能通过阻断MEK-ERK信号传导抑制LPS诱导的TNF-α表达和内毒素休克。(C)2015 Elsevier Inc. All rights reserved.
Lipopolysaccharide (LPS), one of the most prominent pathogen-associated molecular patterns (PAMPs), activates macrophages, causing release of toxic cytokines (i.e. tumor necrosis factor (TNF)-alpha) that may provoke inflammation and endotoxin shock. Here, we tested the potential role of trametinib, a novel and highly potent MAPK/ERK kinase (MEK) inhibitor, against LPS-induced TNF-alpha response in monocytes, and analyzed the underlying mechanisms. We showed that trametinib, at nM concentrations, dramatically inhibited LPS-induced TNF-alpha mRNA expression and protein secretion in transformed (RAW 264.7 cells) and primary murine macrophages. In ex-vivo cultured human peripheral blood mononuclear cells (PBMCs), this MEK inhibitor similarly suppressed INF-alpha production by LPS. For the mechanism study, we found that trametinib blocked LPS-induced MEK-ERK activation in above monocytes, which accounted for the defective TNF-alpha response. Macrophages or PBMCs treated with a traditional MEK inhibitor PD98059 or infected with MEK1/2-shRNA lentivirus exhibited a similar defect as trametinib, and nullified the activity of trametinib. On the other hand, introducing a constitutively-active (CA) ERK1 restored TNF-alpha production by LPS in the presence of trametinib. In vivo, mice administrated with trametinib produced low levels of TNF-alpha after LPS stimulation, and these mice were protected from LPS-induced endotoxin shock. Together, these results show that trametinib inhibits LPS-induced TNF-alpha expression and endotoxin shock probably through blocking MEK-ERK signaling. (C) 2015 Elsevier Inc. All rights reserved.