Yang Qing-Qing, Li Hao-Nan, Xia Yu-Tong, Tian Xue, Feng Fan, Yang Jian, Xu Ya-Li, Guo Juan, Li Xiao-Qi, Wang Jun-Yang, Zeng Xiao-Yan
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.
Front Mol Neurosci. 2022 Apr 8;15:820664. doi: 10.3389/fnmol.2022.820664. eCollection 2022.
Our previous studies have clarified that red nucleus (RN) interleukin (IL)-6 is involved in the maintenance of neuropathic pain and produces a facilitatory effect by activating JAK2/STAT3 and ERK pathways. In this study, we further explored the immune molecular mechanisms of rubral IL-6-mediated descending facilitation at the spinal cord level. IL-6-evoked tactile allodynia was established by injecting recombinant IL-6 into the unilateral RN of naive male rats. Following intrarubral administration of IL-6, obvious tactile allodynia was evoked in the contralateral hindpaw of rats. Meanwhile, the expressions of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), IL-1β, and IL-6 were elevated in the contralateral spinal dorsal horn (L4-L6), blocking spinal TNF-α, IL-1β, or IL-6 with neutralizing antibodies relieved IL-6-evoked tactile allodynia. Conversely, the levels of anti-inflammatory cytokines transforming growth factor-β (TGF-β) and IL-10 were reduced in the contralateral spinal dorsal horn (L4-L6), an intrathecal supplement of exogenous TGF-β, or IL-10 attenuated IL-6-evoked tactile allodynia. Further studies demonstrated that intrarubral pretreatment with JAK2/STAT3 inhibitor AG490 suppressed the elevations of spinal TNF-α, IL-1β, and IL-6 and promoted the expressions of TGF-β and IL-10 in IL-6-evoked tactile allodynia rats. However, intrarubral pretreatment with ERK inhibitor PD98059 only restrained the increase in spinal TNF-α and enhanced the expression of spinal IL-10. These findings imply that rubral IL-6 plays descending facilitation and produces algesic effect through upregulating the expressions of spinal pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 and downregulating the expressions of spinal anti-inflammatory cytokines TGF-β and IL-10 by activating JAK2/STAT3 and/or ERK pathways, which provides potential therapeutic targets for the treatment of pathological pain.
我们之前的研究已经阐明，红核（RN）白细胞介素（IL）-6参与神经性疼痛的维持，并通过激活JAK2/STAT3和ERK通路产生促进作用。在本研究中，我们进一步探讨了红核IL-6介导的脊髓水平下行促进作用的免疫分子机制。通过向未处理的雄性大鼠单侧红核注射重组IL-6建立IL-6诱发的触觉异常性疼痛。在红核内给予IL-6后，大鼠对侧后爪出现明显的触觉异常性疼痛。同时，对侧脊髓背角（L4-L6）中促炎细胞因子肿瘤坏死因子-α（TNF-α）、IL-1β和IL-6的表达升高，用中和抗体阻断脊髓TNF-α、IL-1β或IL-6可减轻IL-6诱发的触觉异常性疼痛。相反，对侧脊髓背角（L4-L6）中抗炎细胞因子转化生长因子-β（TGF-β）和IL-10的水平降低，鞘内补充外源性TGF-β或IL-10可减轻IL-6诱发的触觉异常性疼痛。进一步的研究表明，在IL-6诱发的触觉异常性疼痛大鼠中，红核内预先用JAK2/STAT3抑制剂AG490处理可抑制脊髓TNF-α、IL-1β和IL-6的升高，并促进TGF-β和IL-10的表达。然而，红核内预先用ERK抑制剂PD98059处理仅抑制脊髓TNF-α的增加并增强脊髓IL-10的表达。这些发现表明，红核IL-6发挥下行促进作用，并通过激活JAK2/STAT3和/或ERK通路上调脊髓促炎细胞因子TNF-α、IL-1β和IL-6的表达，下调脊髓抗炎细胞因子TGF-β和IL-10的表达，从而产生痛觉过敏效应，这为病理性疼痛的治疗提供了潜在的治疗靶点。
