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首页> 外文期刊>Neuroscience Letters: An International Multidisciplinary Journal Devoted to the Rapid Publication of Basic Research in the Brain Sciences >Mitogen-activated protein kinase (MAPK) phosphatase-3 (MKP-3) displays a p-JNK-MAPK substrate preference in astrocytes in vitro
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Mitogen-activated protein kinase (MAPK) phosphatase-3 (MKP-3) displays a p-JNK-MAPK substrate preference in astrocytes in vitro

机译：丝裂原激活蛋白激酶（MAPK）磷酸酶3（MKP-3）在体外星形胶质细胞中显示p-JNK-MAPK底物偏好

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摘要

Mitogen-activated protein kinases (MAPKs) play critical roles in the central nervous system immune responses through glial function, which are regulated with relative selectivity (or preference) by MAPK phosphatases (MKP). Phosphorylated extracellular signal-regulated protein kinase (p-ERK) is preferentially dephosphorylated by MKP-3, which display little activity over p-p38 and p-c-Jun NH2-terminal kinases (p-JNK). It has been proposed that these substrate preferences may vary depending on tissue or functional cellular processes. Since astrocytes display a prominent activity of JNK>ERK under stressed or reactive phenotype, we hypothesize that MKP-3 possess a similar or differential substrate preference in astrocytes for JNK and ERK (ERK=JNK or JNK>ERK). We generated transient expression of MKP-3 by transfecting a specific cDNA in primary rat neonatal brain cortex astrocytes. Cells were stimulated with lipopolysaccharide (LPS), and MAPKs and downstream pro-inflammatory products were measured by Western blot and ELISA analyses. MKP-3 expression in primary astrocytes reduced LPS-induced p-ERK and p-p38 by ~50%, and p-JNK by approx75%, and moderately reduced nitrite oxide (NO), while completely blocked Interleukin (IL)-6 and tumor necrosis factor alpha (TNFalpha). We confirmed MKP-3 specific activity by developing a BV-2 microglia cell line stably overexpressing MKP-3 and using a specific siRNA against MKP-3. Our data demonstrate MKP-3 has differential substrate preference in astrocytes compared to other cells types, since it preferentially dephosphorylated p-JNK over p-ERK. Our results indicate also that astrocytic immune functions can be modulated by MKP-3 induction, a strategy that could be beneficial in neurological conditions in which astrocytes play a pathophysiological role, i.e. persistent pain.
机译：丝裂原激活的蛋白激酶（MAPKs）通过神经胶质功能在中枢神经系统免疫反应中起关键作用，而神经胶质功能由MAPK磷酸酶（MKP）相对选择性（或偏好）调节。磷酸化的细胞外信号调节蛋白激酶（p-ERK）被MKP-3优先去磷酸化，与p-p38和p-c-Jun NH2末端激酶（p-JNK）相比，其活性很小。已经提出这些底物偏好可以根据组织或功能性细胞过程而变化。由于星形胶质细胞在应激或反应性表型下显示出JNK> ERK的显着活性，因此我们假设MKP-3在星形胶质细胞中对JNK和ERK具有相似或不同的底物偏好（ERK = JNK或JNK> ERK）。通过在原代大鼠新生大脑皮层星形胶质细胞中转染特定的cDNA，我们产生了MKP-3的瞬时表达。用脂多糖（LPS）刺激细胞，并通过Western印迹和ELISA分析测量MAPK和下游促炎产物。 MKP-3在原代星形胶质细胞中的表达将LPS诱导的p-ERK和p-p38降低约50％，将p-JNK降低约75％，并适度降低亚硝酸盐（NO），同时完全阻断白介素（IL）-6和肿瘤坏死因子α（TNFalpha）。我们通过开发稳定过量表达MKP-3的BV-2小胶质细胞系并使用针对MKP-3的特异性siRNA证实了MKP-3的特异性活性。我们的数据表明，与其他细胞类型相比，MKP-3在星形胶质细胞中具有不同的底物偏好，因为它优先于p-ERK磷酸化p-JNK。我们的结果还表明，星形胶质细胞免疫功能可以通过MKP-3诱导来调节，该策略在星形胶质细胞发挥病理生理作用（即持续性疼痛）的神经系统疾病中可能是有益的。

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