Upregulation of CCL2 via ATF3/c-Jun interaction mediated the Bortezomib-induced peripheral neuropathy
Upregulation of CCL2 via ATF3/c-Jun interaction mediated the Bortezomib-induced peripheral neuropathy
复制标题
通过 ATF3/c-Jun 相互作用上调 CCL2 介导硼替佐米诱导的周围神经病变
DOI：
10.1016/j.bbi.2015.11.004
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发表时间：
2016-03-01
影响因子：
15.1
通讯作者：
Xin, Wenjun
中科院分区：
文献类型：
--
作者：
Liu, Cuicui;Luan, Shuo;Xin, Wenjun
硼替佐米是一种常用的化疗药物，用于治疗难治性多发性骨髓瘤和血液肿瘤。BTZ引起疼痛性周围神经病变的机制尚不清楚。在本研究中，我们发现连续5天以0.4 mg/kg剂量施用BTZ可显著增加DRG中CCL2的表达，鞘内给予CCL2中和抗体可抑制BTZ引起的机械性异常痛。我们还发现c-Jun在DRG中的表达增加，并且c-Jun信号的抑制阻止了BTZ治疗大鼠的CCL2上调和机械异常性痛。此外，体外荧光素酶实验和体内ChIP实验结果表明，c-Jun可能通过直接结合CCL2启动子的特定位置，对btz诱导的CCL2上调至关重要。此外，本研究结果显示，ATF3在DRG神经元中与c-Jun共表达上调，BTZ处理后大鼠DRG中c-Jun与ATF3的相互作用增强。重要的是，在BTZ处理的大鼠中，ATF3 siRNA预处理显著抑制了c-Jun向ccl2启动子的募集。综上所述，这些发现表明，由于c-Jun和ATF3在DRG中的相互作用增强，CCL2的上调有助于btz诱导的机械异常性疼痛。(C) 2015出版的爱思唯尔公司。
Bortezomib (BTZ) is a frequently used chemotherapeutic drug for the treatment of refractory multiple myeloma and hematological neoplasms. The mechanism by which the administration of BTZ leads to painful peripheral neuropathy remains unclear. In present study, we found that application of BTZ at 0.4 mg/kg for consecutive 5 days significantly increased the expression of CCL2 in DRG, and intrathecal administration of neutralizing antibody against CCL2 inhibited the mechanical allodynia induced by BTZ. We also found an increased expression of c-Jun in DRG, and that inhibition of c-Jun signaling prevented the CCL2 upregulation and mechanical allodynia in the rats treated with BTZ. Furthermore, the results with luciferase assay in vitro and ChIP assay in vivo showed that c-Jun might be essential for BTZ-induced CCL2 upregulation via binding directly to the specific position of the ccl2 promoter. In addition, the present results showed that an upregulated expression of ATF3 was co-expressed with c-Jun in the DRG neurons, and the enhanced interaction between c-Jun and ATF3 was observed in DRG in the rats treated with BTZ. Importantly, pretreatment with ATF3 siRNA significantly inhibited the recruitment of c-Jun to the ccl2 promoter in the rats treated with BTZ. Taken together, these findings suggested that upregulation of CCL2 resulting from the enhanced interaction between c-Jun and ATF3 in DRG contributed to BTZ-induced mechanical allodynia. (C) 2015 Published by Elsevier Inc.