Intrathecal interleukin-10 gene therapy attenuates paclitaxel-induced mechanical allodynia and proinflammatory cytokine expression in dorsal root ganglia in rats
Intrathecal interleukin-10 gene therapy attenuates paclitaxel-induced mechanical allodynia and proinflammatory cytokine expression in dorsal root ganglia in rats
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DOI：
10.1016/j.bbi.2006.10.012
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发表时间：
2007-07-01
影响因子：
15.1
通讯作者：
Watkins, Linda R.
中科院分区：
文献类型：
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作者：
Ledeboer, Annemarie;Jekich, Brian M.;Watkins, Linda R.
紫杉醇是一种常用的癌症化疗药物，经常引起疼痛的周围神经病变。这种剂量限制性副作用的机制知之甚少。越来越多的证据支持，促炎细胞因子，如白细胞介素-1（IL-1）和肿瘤坏死因子（TNF），释放激活的脊髓胶质细胞和背根神经节（DRG）内是至关重要的，在增强疼痛的各种动物模型的神经性疼痛。这些细胞因子是否参与紫杉醇诱导的神经病变尚不清楚。在这里，使用大鼠神经病理性疼痛模型诱导的反复全身紫杉醇注射，我们检查是否紫杉醇上调促炎细胞因子基因的表达，以及这些变化和紫杉醇诱导的机械性异常性疼痛是否可以通过鞘内IL-1受体拮抗剂（IL-1 ra）或鞘内递送编码抗炎细胞因子白细胞介素-10（IL-10）的质粒DNA来减弱。数据显示紫杉醇治疗诱导腰椎DRG中IL-1、TNF和免疫细胞标志物的mRNA表达。鞘内IL-1 ra逆转了紫杉醇诱导的异常性疼痛，鞘内IL-10基因治疗预防并逐步逆转了这种异常性疼痛状态。此外，IL-10基因治疗导致腰椎背根神经节和脑膜中IL-10 mRNA水平增加，治疗开始后2周测量，而紫杉醇诱导的腰椎背根神经节中IL-1，TNF和CD 11b mRNA的表达显著降低。总之，这些数据支持紫杉醇诱导的神经性疼痛是由促炎细胞因子介导的，可能是由DRG中激活的免疫细胞释放的。我们建议，靶向产生促炎细胞因子的鞘内IL-10基因治疗可能是一个有前途的治疗策略，为缓解紫杉醇诱导的神经病理性疼痛。(c)2006爱思唯尔公司All rights reserved.
Paclitaxel is a commonly used cancer chemotherapy drug that frequently causes painful peripheral neuropathies. The mechanisms underlying this dose-limiting side effect are poorly understood. Growing evidence supports that proinflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF), released by activated spinal glial cells and within the dorsal root ganglia (DRG) are critical in enhancing pain in various animal models of neuropathic pain. Whether these cytokines are involved in paclitaxel-induced neuropathy is unknown. Here, using a rat neuropathic pain model induced by repeated systemic paclitaxel injections, we examined whether paclitaxel upregulates proinflammatory cytokine gene expression, and whether these changes and paclitaxel-induced mechanical allodynia can be attenuated by intrathecal IL-1 receptor antagonist (IL-1ra) or intrathecal delivery of plasmid DNA encoding the anti-inflammatory cytokine, interleukin-10(IL-10). The data show that paclitaxel treatment induces mRNA expression of IL-1, TNF, and immune cell markers in lumbar DRG. Intrathecal IL-1ra reversed paclitaxel-induced allodynia and intrathecal IL-10 gene therapy both prevented, and progressively reversed, this allodynic state. Moreover, IL-10 gene therapy resulted in increased IL-10 mRNA levels in lumbar DRG and meninges, measured 2 weeks after initiation of therapy, whereas paclitaxel-induced expression of IL-1, TNF, and CD11b mRNA in lumbar DRG was markedly decreased. Taken together, these data support that paclitaxel-induced neuropathic pain is mediated by proinflammatory cytokines, possibly released by activated immune cells in the DRG. We propose that targeting the production of proinflammatory cytokines by intrathecal IL-10 gene therapy may be a promising therapeutic strategy for the relief of paclitaxel-induced neuropathic pain. (c) 2006 Elsevier Inc. All rights reserved.