Department of Spine Surgery, the Second Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China.
Department of Pathogen Biology, Medical College, Nantong University, Nantong, 226001, Jiangsu, China.
Neurochem Res. 2018 Aug;43(8):1631-1640. doi: 10.1007/s11064-018-2578-8. Epub 2018 Jun 22.
E3 ubiquitin ligase c-Caritas B cell lymphoma (c-cbl) is associated with negative regulation of receptor tyrosine kinases, signal transduction of antigens and cytokine receptors, and immune response. However, the expression and function of c-cbl in the regulation of neuropathic pain after chronic constriction injury (CCI) are unknown. In rat CCI model, c-cbl inhibited the activation of spinal cord microglia and the release of pro-inflammatory factors including tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β) and interleukin 6 (IL-6), which alleviated mechanical and heat pain through down-regulating extracellular signal-regulated kinase (ERK) pathway. Additionally, exogenous TNF-α inhibited c-cbl protein level vice versa. In the primary microglia transfected with c-cbl siRNA, when treated with TNF-α or TNF-α inhibitor, the corresponding secretion of IL-1β and IL-6 did not change. In summary, CCI down-regulated c-cbl expression and induced the activation of microglia, then activated microglia released inflammatory factors via ERK signaling to cause pain. Our data might supply a novel molecular target for the therapy of CCI-induced neuropathic pain.
E3 泛素连接酶 c-Caritas B 细胞淋巴瘤 (c-cbl) 与受体酪氨酸激酶的负调控、抗原和细胞因子受体的信号转导以及免疫反应有关。然而，c-cbl 在慢性压迫损伤 (CCI) 后神经性疼痛调节中的表达和功能尚不清楚。在大鼠 CCI 模型中，c-cbl 抑制脊髓小胶质细胞的激活和促炎因子的释放，包括肿瘤坏死因子-α (TNF-α)、白细胞介素 1β (IL-1β) 和白细胞介素 6 (IL-6)，通过下调细胞外信号调节激酶 (ERK) 通路减轻机械和热痛。此外，外源性 TNF-α 抑制 c-cbl 蛋白水平。在转染 c-cbl siRNA 的原代小胶质细胞中，用 TNF-α 或 TNF-α 抑制剂处理时，IL-1β 和 IL-6 的相应分泌没有变化。总之，CCI 下调 c-cbl 的表达并诱导小胶质细胞的激活，然后激活的小胶质细胞通过 ERK 信号释放炎症因子引起疼痛。我们的数据可能为 CCI 诱导的神经性疼痛的治疗提供了一个新的分子靶点。
