EphrinB-EphB receptor signaling contributes to bone cancer pain via Toll-like receptor and proinflammatory cytokines in rat spinal cord
EphrinB-EphB receptor signaling contributes to bone cancer pain via Toll-like receptor and proinflammatory cytokines in rat spinal cord
复制标题
EphrinB-EphB 受体信号传导通过大鼠脊髓中的 Toll 样受体和促炎细胞因子导致骨癌疼痛
DOI：
10.1016/j.pain.2013.08.017
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发表时间：
2013-12-01
期刊：
影响因子：
7.4
通讯作者：
Song, Xue-Jun
中科院分区：
文献类型：
--
作者：
Liu, Su;Liu, Yue-Peng;Song, Xue-Jun
治疗骨癌疼痛是一个重大的临床挑战，骨癌疼痛的潜在机制仍然难以捉摸。EphrinB-EphB受体信号可能通过N-甲基-D-天冬氨酸受体神经元机制参与骨癌疼痛。在这里，我们报告ephrinB-EphB信号也可以通过Toll样受体4（TLR 4）-神经胶质细胞机制在脊髓中发挥作用。采用大鼠胫骨骨腔肿瘤细胞植入法（TCI）诱发骨癌痛。TCI增加了TLR 4和EphB 1受体的表达，星形胶质细胞和小胶质细胞的活化，以及白细胞介素-1 β（IL-1 β）和肿瘤坏死因子-α（TNF-α）的水平增加。TLR 4和EphB 1的表达增加在星形胶质细胞和小胶质细胞中相互共存。脊髓敲低TLR 4抑制了TCI诱导的骨癌疼痛行为体征。TCI诱导的星形胶质细胞和小胶质细胞的活化以及IL-1 β和TNF-α水平的增加分别通过鞘内施用靶向TLR 4的siRNA 2和EphB受体拮抗剂EphB 2-Fc来抑制。EphB 2-Fc的施用抑制了TCI诱导的TLR 4表达的增加，但siRNA 2未能影响TCI诱导的EphB 1表达。鞘内注射外源性EphB 1受体激活剂ephrinB 2-Fc可增加TLR 4的表达以及IL-1 β和TNF-α的水平，激活星形胶质细胞和小胶质细胞，并诱导热超敏反应。这些ephrinB 2-Fc诱导的改变被脊髓TLR 4敲低所抑制。这项研究表明，TLR 4可能是一个潜在的目标，用于预防或逆转骨癌疼痛和其他类似的疼痛过程介导的ephrinB-EphB受体信号。(C)2013年国际疼痛研究协会。Elsevier B. V.出版，保留所有权利。
Treating bone cancer pain poses a major clinical challenge, and the mechanisms underlying bone cancer pain remain elusive. EphrinB-EphB receptor signaling may contribute to bone cancer pain through N-methyl-D-aspartate receptor neuronal mechanisms. Here, we report that ephrinB-EphB signaling may also act through a Toll-like receptor 4 (TLR4)-glial cell mechanism in the spinal cord. Bone cancer pain was induced by tibia bone cavity tumor cell implantation (TCI) in rats. TCI increased the expression of TLR4 and the EphB1 receptor, the activation of astrocytes and microglial cells, and increased levels of interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha). The increased expression of TLR4 and EphB1 were colocalized with each other in astrocytes and microglial cells. Spinal knockdown of TLR4 suppressed TCI-induced behavioral signs of bone cancer pain. The TCI-induced activation of astrocytes and microglial cells, as well as the increased levels of IL-1 beta and TNF-alpha, were inhibited by intrathecal administration of TLR4-targeting siRNA2 and the EphB receptor antagonist EphB2-Fc, respectively. The administration of EphB2-Fc suppressed the TCI-induced increase of TLR4 expression but siRNA2 failed to affect TCI-induced EphB1 expression. Intrathecal administration of an exogenous EphB1 receptor activator, ephrinB2-Fc, increased the expression of TLR4 and the levels of IL-1 beta and TNF-alpha, activated astrocytes and microglial cells, and induced thermal hypersensitivity. These ephrinB2-Fc-induced alterations were suppressed by spinal knockdown of TLR4. This study suggests that TLR4 may be a potential target for preventing or reversing bone cancer pain and other similar painful processes mediated by ephrinB-EphB receptor signaling. (C) 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.