MAPK-activated protein kinase 2 deficiency in microglia inhibits pro-inflammatory mediator release and resultant neurotoxicity - Relevance to neuroinflammation in a transgenic mouse model of Alzheimer disease
MAPK-activated protein kinase 2 deficiency in microglia inhibits pro-inflammatory mediator release and resultant neurotoxicity - Relevance to neuroinflammation in a transgenic mouse model of Alzheimer disease
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DOI：
10.1074/jbc.m513646200
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发表时间：
2006-08-18
影响因子：
4.8
通讯作者：
Richardson, Jill C.
中科院分区：
文献类型：
--
作者：
Culbert, Ainsley A.;Skaper, Stephen D.;Richardson, Jill C.
MAPK激活的蛋白激酶2(MAPKAPK2或MK2)是由p38MAPK直接调节的几种蛋白激酶之一。P38MAPK在阿尔茨海默病(AD)发病机制中的作用已被提出。在这里，我们提供的证据表明，MK2也在与AD相关的神经炎性和神经退行性病变中发挥作用。在脂多糖(LPS)+干扰素-γ刺激的小胶质细胞中，MK2的激活和表达增加，提示MK2在引发促炎反应中起作用。与MK2(+/+)野生型小胶质细胞相比，MK2(-/-)小鼠体外培养的小胶质细胞在LPS+干扰素-γ或淀粉样β蛋白(1-42)刺激下，对肿瘤坏死因子α、KC(与人GROS和IL-8序列同源性最高的小鼠趋化因子)和巨噬细胞炎性蛋白1α的释放有显著的抑制作用。与抑制促炎介质释放一致，与脂多糖+干扰素γ刺激或淀粉样β蛋白(1-42)刺激的MK2(+/+)小胶质细胞共培养的皮质神经元可免受小胶质细胞介导的神经细胞毒性。在转基因AD小鼠模型中，携带家族性AD突变的淀粉样前体蛋白和早老素-1在大脑的特定区域过表达，MK2的激活和表达增加与相同脑区的β-淀粉样蛋白沉积、小胶质细胞激活和肿瘤坏死因子α、巨噬细胞炎性蛋白1α和KC基因的表达上调有关。我们的数据表明MK2在AD脑病理中的作用，涉及细胞因子和趋化因子的神经炎症和明显的神经元丢失已被记录在案。
MAPK-activated protein kinase 2 (MAPKAP K2 or MK2) is one of several kinases directly regulated by p38 MAPK. A role for p38 MAPK in the pathology of Alzheimer disease (AD) has previously been suggested. Here, we provide evidence to suggest that MK2 also plays a role in neuroinflammatory and neurodegenerative pathology of relevance to AD. MK2 activation and expression were increased in lipopolysaccharide (LPS) + interferon gamma-stimulated microglial cells, implicating a role for MK2 in eliciting a pro-inflammatory response. Microglia cultured ex vivo from MK2-deficient (MK2(-/-)) mice demonstrated significant inhibition in release of tumor necrosis factor alpha, KC (mouse chemokine with highest sequence identity to human GROs and interleukin-8), and macrophage inflammatory protein 1 alpha on stimulation with LPS + interferon gamma or amyloid-beta peptide (1-42) compared with MK2(+/+) wild-type microglia. Consistent with an inhibition in pro- inflammatory mediator release, cortical neurons co-cultured with LPS + interferon gamma-stimulated or amyloid-beta peptide (1-42) stimulated MK2(+/+) microglia were protected from microglial-mediated neuronal cell toxicity. In a transgenic mouse model of AD in which amyloid precursor protein and presenilin-1 harboring familial AD mutations are over-expressed in specific regions of the brain, elevated activation and expression of MK2 correlated with beta-amyloid deposition, microglial activation, and up-regulation of tumor necrosis factor alpha, macrophage inflammatory protein 1 alpha, and KC gene expression in the same brain regions. Our data propose a role for MK2 in AD brain pathology, for which neuroinflammation involving cytokines and chemokines and overt neuronal loss have been documented.