Department of Laboratory Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Department of Pathogenic Biology and Immunology, Xi'an Jiaotong University Health Science Center, Xi'an, China.
Neuropathology. 2020 Aug;40(4):347-357. doi: 10.1111/neup.12653. Epub 2020 May 7.
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.
我们之前曾报道过，红核（RN）中的白细胞介素（IL）-6 参与了 spared nerve injury（SNI）诱导的神经性疼痛的维持，并通过 Janus-activated kinase 2/signal transducer and activator of transcription 3（JAK2/STAT3）和细胞外信号调节激酶（ERK）信号转导通路发挥促进作用。本研究旨在探讨肿瘤坏死因子-α（TNF-α）和 IL-1β 在 RN IL-6 介导的神经性疼痛维持中的作用及其相关信号转导通路。与 SNI 后 3 周 RN IL-6 水平升高相似，神经损伤后 3 周，对侧 RN 中 TNF-α 和 IL-1β 的蛋白水平也升高。TNF-α 和 IL-1β 的上调与 IL-6 密切相关，并被 RN 内注射中和抗体 IL-6 抑制。给予 SNI 大鼠 RN 中 JAK2 拮抗剂 AG490 或 ERK 拮抗剂 PD98059 可显著增加 paw withdrawal threshold（PWT），并抑制局部 TNF-α 和 IL-1β 的上调。进一步的实验表明，在正常大鼠的 RN 内注射外源性 IL-6 明显降低了对侧后爪的 PWT，并增强了局部 TNF-α 和 IL-1β 的表达。AG490 的预处理可阻断 IL-6 诱导的触觉过敏，并抑制 TNF-α 和 IL-1β 的上调。然而，预先给予 PD98059 仅抑制了 IL-1β 的上调，而不影响 TNF-α。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，通过 JAK2/STAT3 和 ERK 通路诱导 IL-1β 的产生。
