We previously reported that interleukin (IL)‐6 in the red nucleus (RN) is involved in the maintenance of neuropathic pain induced by spared nerve injury (SNI), and exerts a facilitatory effect via Janus‐activated kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) and extracellular signal‐regulated kinase (ERK) signal transduction pathways. The present study aimed at investigating the roles of tumor necrosis factor‐α (TNF‐α) and IL‐1β in RN IL‐6‐mediated maintenance of neuropathic pain and related signal transduction pathways. Being similar to the elevation of RN IL‐6 three weeks after SNI, increased protein levels of both TNF‐α and IL‐1β were also observed in the contralateral RN three weeks after the nerve injury. The upregulations of TNF‐α and IL‐1β were closely correlative with IL‐6 and suppressed by intrarubral injection of a neutralizing antibody against IL‐6. Administration of either the JAK2 antagonist AG490 or the ERK antagonist PD98059 to the RN of rats with SNI remarkably increased the paw withdrawal threshold (PWT) and inhibited the up‐regulations of local TNF‐α and IL‐1β. Further experiments indicated that intrarubral injection of exogenous IL‐6 in naive rats apparently lowered the PWT of the contralateral hindpaw and boosted the local expressions of TNF‐α and IL‐1β. Pretreatment with AG490 could block IL‐6‐induced tactile hypersensitivity and suppress the up‐regulations of both TNF‐α and IL‐1β. However, injection of PD98059 in advance only inhibited the upregulation of IL‐1β, but not TNF‐α. These findings indicate that RN IL‐6 mediates the maintenance of neuropathic pain by inducing the productions of TNF‐α and IL‐1β. IL‐6 induces the expression of TNF‐α through the JAK2/STAT3 pathway, and the production of IL‐1β through the JAK2/STAT3 and ERK pathways.

中文翻译：

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红核 IL-6 通过 JAK2/STAT3 和 ERK 信号通路诱导 TNF-α 和 IL-1β 的产生，介导神经性疼痛的维持

我们之前报道过，红核 (RN) 中的白细胞介素 (IL)-6 参与维持由幸免神经损伤 (SNI) 引起的神经性疼痛，并通过 Janus 激活激酶 2/信号转导和激活剂发挥促进作用转录 3 (JAK2/STAT3) 和细胞外信号调节激酶 (ERK) 信号转导通路。本研究旨在研究肿瘤坏死因子-α (TNF-α) 和 IL-1β 在 RN IL-6 介导的神经病理性疼痛维持和相关信号转导通路中的作用。与 SNI 后 3 周 RN IL-6 升高类似，神经损伤后 3 周，在对侧 RN 中也观察到 TNF-α 和 IL-1β 蛋白水平升高。TNF-α 和 IL-1β 的上调与 IL-6 密切相关，并通过红血球内注射针对 IL-6 的中和抗体加以抑制。将 JAK2 拮抗剂 AG490 或 ERK 拮抗剂 PD98059 施用于 SNI 大鼠的 RN，显着增加了缩爪阈值 (PWT)，并抑制了局部 TNF-α 和 IL-1β 的上调。进一步的实验表明，外源性IL-6在幼稚大鼠的红血球内注射明显降低了对侧后爪的PWT，并促进了TNF-α和IL-1β的局部表达。用 AG490 预处理可以阻断 IL-6 诱导的触觉超敏反应并抑制 TNF-α 和 IL-1β 的上调。然而，预先注射PD98059只能抑制IL-1β的上调，而不能抑制TNF-α的上调。这些发现表明，RN IL-6 通过诱导 TNF-α 和 IL-1β 的产生来介导神经性疼痛的维持。IL-6 通过 JAK2/STAT3 通路诱导 TNF-α 的表达，并通过 JAK2/STAT3 和 ERK 通路诱导 IL-1β 的产生。