Institute of Physiology1/Neurophysiology, Jena University Hospital, Friedrich-Schiller-University of Jena, Jena, Germany.
J Neurochem. 2021 Aug;158(4):898-911. doi: 10.1111/jnc.15438. Epub 2021 Jun 28.
Both spinal tumor necrosis factor (TNF) and interleukin-6 (IL-6) contribute to the development of "mechanical" spinal hyperexcitability in inflammatory pain states. Recently, we found that spinal sensitization by TNF was significantly reduced by blockade of spinal IL-6 signaling suggesting that IL-6 signaling is involved in spinal TNF effects. Here, we explored whether spinal interleukin-1β (IL-1β), also implicated in inflammatory pain, induces "mechanical" spinal hyperexcitability, and whether spinal IL-1β effects are related to TNF and IL-6 effects. We recorded the responses of spinal cord neurons to mechanical stimulation of the knee joint in vivo and used cellular approaches on microglial and astroglial cell lines to identify interactions of IL-1β, TNF, and IL-6. Spinal application of IL-1β in anesthetized rats modestly enhanced responses of spinal cord neurons to innocuous and noxious mechanical joint stimulation. This effect was blocked by minocycline indicating microglia involvement, and significantly attenuated by interfering with IL-6 signaling. In the BV2 microglial cell line, IL-1β, like TNF, enhanced the release of soluble IL-6 receptor, necessary for spinal IL-6 actions. Different to TNF, IL-1β caused SNB-19 astrocytes to release interleukin-11. The generation of "mechanical" spinal hyperexcitability by IL-1β was more pronounced upon spinal TNF neutralization with etanercept, suggesting that concomitant TNF limits IL-1β effects. In BV2 cells, TNF stimulated the release of IL-1Ra, an endogenous IL-1β antagonist. Thus, spinal IL-1β has the potential to induce spinal hyperexcitability sharing with TNF dependency on IL-6 signaling, but TNF also limited IL-1β effects explaining the modest effect of IL-1β.
脊髓肿瘤坏死因子 (TNF) 和白细胞介素-6 (IL-6) 均可导致炎症性疼痛状态下的“机械性”脊髓过度兴奋。最近，我们发现 TNF 诱导的脊髓敏化作用可显著被 IL-6 信号阻断所抑制，这表明 IL-6 信号参与了 TNF 的脊髓效应。在此，我们探讨了脊髓白细胞介素-1β (IL-1β) 是否也参与了炎症性疼痛，是否会引起“机械性”脊髓过度兴奋，以及脊髓 IL-1β 效应是否与 TNF 和 IL-6 效应有关。我们在体内记录了膝关节机械刺激对脊髓神经元的反应，并在小胶质细胞和星形胶质细胞系上使用细胞方法来鉴定 IL-1β、TNF 和 IL-6 之间的相互作用。在麻醉大鼠中脊髓应用 IL-1β 可适度增强脊髓神经元对无害和有害机械关节刺激的反应。该作用可被米诺环素阻断，表明小胶质细胞参与其中，并且可被干扰 IL-6 信号显著减弱。在 BV2 小胶质细胞系中，IL-1β 像 TNF 一样，增强了可溶性 IL-6 受体的释放，这是脊髓 IL-6 作用所必需的。与 TNF 不同，IL-1β 引起 SNB-19 星形胶质细胞释放白细胞介素-11。在依那西普中和 TNF 后，IL-1β 引起的“机械性”脊髓过度兴奋更为明显，这表明同时存在的 TNF 限制了 IL-1β 的作用。在 BV2 细胞中，TNF 刺激 IL-1Ra 的释放，IL-1Ra 是 IL-1β 的内源性拮抗剂。因此，脊髓 IL-1β 具有诱导脊髓过度兴奋的潜力，与 TNF 对 IL-6 信号的依赖性相同，但 TNF 也限制了 IL-1β 的作用，这解释了 IL-1β 的作用较为温和的原因。
