AKAP150 involved in paclitaxel-induced neuropathic pain via inhibiting CN/NFAT2 pathway and downregulating IL-4
AKAP150 involved in paclitaxel-induced neuropathic pain via inhibiting CN/NFAT2 pathway and downregulating IL-4
复制标题
AKAP150 通过抑制 CN/NFAT2 通路和下调 IL-4 参与紫杉醇诱导的神经性疼痛
DOI：
10.1016/j.bbi.2017.10.015
复制
发表时间：
2018-02-01
影响因子：
15.1
通讯作者：
Ouyang, Handong
中科院分区：
文献类型：
--
作者：
Nie, Bilin;Liu, Cuicui;Ouyang, Handong
抗微管蛋白化学治疗剂，例如紫杉醇，是用于癌症治疗的有效化学治疗药物。然而，疼痛性神经病变是限制化疗药物更广泛应用的主要不良反应。在这项研究中，我们发现A-激酶锚蛋白150（AKAP 150）在紫杉醇注射后显著上调。通过siRNA或AKAP 150（flox/flox）抑制啮齿动物中的AKAP 150可减轻紫杉醇诱导的疼痛行为，并部分恢复紫杉醇治疗后降低的钙调神经磷酸酶（CN）活性。紫杉醇降低抗炎细胞因子白细胞介素4（IL-4）的表达，鞘内注射IL-4可有效减轻紫杉醇诱导的超敏反应和背根神经节（DRG）神经元动作电位频率。CN酶活性降低，导致细胞核中活化T细胞核因子2（NFAT 2）蛋白表达减少。染色质免疫沉淀显示，NFAT 2与IL-4基因启动子结合，调节IL-4蛋白的表达。通过鞘内注射AAV 5-NFAT 2-GFP病毒过表达NFAT 2可通过增加IL-4的表达减轻紫杉醇诱导的疼痛行为。用siRNA或AAV 5-Cre-GFP敲低AKAP 150后，DRG中IL-4的表达部分恢复。我们的研究结果表明，通过由AKAP 150介导的CN/NFAT 2途径调节IL-4可能是紫杉醇诱导的神经性疼痛和/或其他神经精神疾病的关键治疗靶点。(C)2017爱思唯尔公司All rights reserved.
Antitubulin chemotherapeutics agents, such as paclitaxel, are effective chemotherapy drugs for cancer treatment. However, painful neuropathy is a major adverse effect limiting the wider application of chemotherapeutics. In this study, we found that A-kinase anchor protein 150 (AKAP150) was significantly upregulated after paclitaxel injection. Inhibition of AKAP150 via siRNA or AKAP150(flox/flox) in rodents alleviated the pain behavior induced by paclitaxel, and partly restored the decreased calcineurin (CN) phosphatase activity after paclitaxel treatment. Paclitaxel decreased the expression of anti-inflammatory cytokine interleukin-4 (IL-4), and intrathecal injections of IL-4 effectively alleviated paclitaxel-induced hypersensitivity and the frequency of dorsal root ganglion (DRG) neurons action potential. The decreased CN enzyme activity, resulted in reduced protein expression of nuclear factor of activated T cells 2 (NFAT2) in cell nuclei. Chromatin immunoprecipitation showed that, NFAT2 binds to the IL-4 gene promoter regulating the protein expression of IL-4. Overexpression of NFAT2 by intrathecal injection of the AAV5-NFAT2-GFP virus alleviated the pain behavior induced by paclitaxel via increasing the expression of IL-4. Knocked down AKAP150 by siRNA or AAV5-Cre-GFP partly restored the expression of IL-4 in DRG. Our results indicated that regulation of IL-4 via the CN/NFAT2 pathway mediated by AKAP150 could be a pivotal treatment target for paclitaxel-induced neuropathic pain and or other neuropsychiatric disorders. (C) 2017 Elsevier Inc. All rights reserved.