Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, P.O. Box 80260, Jeddah 21589, Saudi Arabia.
Strathclyde Institute for Pharmacy & Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK.
Int J Mol Sci. 2019 Jul 12;20(14):3434. doi: 10.3390/ijms20143434.
Mitogen-activated protein kinase phosphatase-2 (MKP-2) is a type 1 nuclear dual specific phosphatase (DUSP-4). It plays an important role in macrophage inflammatory responses through the negative regulation of Mitogen activated protein kinase (MAPK) signalling. However, information on the effect of MKP-2 on other aspect of macrophage function is limited.
We investigated the impact of MKP-2 in the regulation of several genes that are involved in function while using comparative whole genome microarray analysis in macrophages from MKP-2 wild type (wt) and knock out (ko) mice.
Our data showed that the lack of MKP-2 caused a significant down-regulation of colony-stimulating factor-2 () and monocyte to macrophage-associated differentiation () genes, suggesting a role of MKP-2 in macrophage development. When treated with macrophage colony stimulating factor (M-CSF), and mRNA levels increased but significantly reduced in ko cells in comparison to wt counterparts. This effect of MKP-2 deletion on macrophage function was also observed by cell counting and DNA measurements. On the signalling level, M-CSF stimulation induced extracellular signal-regulated kinases (ERK) phosphorylation, which was significantly enhanced in the absence of MKP-2. Pharmacological inhibition of ERK reduced both and genes in both wild type and ko cultures, which suggested that enhanced ERK activation in ko cultures may not explain effects on gene expression. Interestingly other functional markers were also shown to be reduced in ko macrophages in comparison to wt mice; the expression of CD115, which is a receptor for M-CSF, and CD34, a stem/progenitor cell marker, suggesting global regulation of gene expression by MKP-2.
Transcriptome profiling reveals that MKP-2 regulates macrophage development showing candidate targets from monocyte-to-macrophage differentiation and macrophage proliferation. However, it is unclear whether effects upon ERK signalling are able to explain the effects of DUSP-4 deletion on macrophage function.
丝裂原活化蛋白激酶磷酸酶-2（MKP-2）是一种 1 型核双特异性磷酸酶（DUSP-4）。它通过负调控丝裂原活化蛋白激酶（MAPK）信号转导，在巨噬细胞炎症反应中发挥重要作用。然而，关于 MKP-2 对巨噬细胞功能其他方面的影响的信息有限。
我们使用 MKP-2 野生型（wt）和敲除（ko）小鼠的巨噬细胞比较全基因组微阵列分析，研究了 MKP-2 在调节几个参与功能的基因中的影响。
我们的数据表明，缺乏 MKP-2 导致集落刺激因子-2（）和单核细胞向巨噬细胞相关分化（）基因的显著下调，表明 MKP-2 在巨噬细胞发育中起作用。用巨噬细胞集落刺激因子（M-CSF）处理时，与 wt 细胞相比，ko 细胞中的 和 mRNA 水平增加，但显著降低。MKP-2 缺失对巨噬细胞功能的这种影响也通过细胞计数和 DNA 测量观察到。在信号转导水平上，M-CSF 刺激诱导细胞外信号调节激酶（ERK）磷酸化，在缺乏 MKP-2 的情况下显著增强。ERK 的药理学抑制减少了野生型和 ko 培养物中的 和 基因，这表明 ko 培养物中增强的 ERK 激活不能解释基因表达的影响。有趣的是，与 wt 小鼠相比，ko 巨噬细胞中的其他功能标记物也减少；M-CSF 的受体 CD115 和干细胞/祖细胞标记物 CD34 的表达减少，表明 MKP-2 对基因表达的全面调控。
转录组谱分析显示，MKP-2 调节巨噬细胞发育，显示单核细胞向巨噬细胞分化和巨噬细胞增殖的候选靶标。然而，尚不清楚 ERK 信号转导的影响是否能够解释 DUSP-4 缺失对巨噬细胞功能的影响。
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