在肿瘤细胞中，白细胞介素 6 (IL-6) 信号传导可导致表皮生长因子受体 (EGFR) 激活，从而延长 Stat3 的激活时间。在本实验中，我们测试了 IL-6 信号传导在外周和脊髓伤害感受中激活 EGFR 信号传导的假设，并检查了 EGFR 定位和激活是否与关节炎中的疼痛相关行为一致。在麻醉大鼠体内，脊柱应用 EGFR 受体阻滞剂吉非替尼可降低脊髓神经元对有害关节刺激的反应，但前提是用 IL-6 和可溶性 IL-6 受体对脊柱进行预处理。使用蛋白质印迹，我们发现吉非替尼在 BV2 细胞系的小胶质细胞中减少了 IL-6 诱导的 Stat3 激活，但在培养的 DRG 神经元中却没有减少。免疫组织化学显示 EGFR 定位于正常大鼠的大多数 DRG 神经元中，但在急性和最疼痛的关节炎阶段显着下调。在小鼠脊髓中，EGFR 主要在炎症慢性期高度激活，并定位于神经元。这些数据表明脊髓 IL-6 信号传导可能激活脊髓 EGFR 信号传导。急性关节炎中 DRG 神经元中 EGFR 的下调可能会限制伤害感受，但脊髓中 EGFR 的明显延迟激活可能与慢性炎性疼痛有关。

In tumor cells, interleukin-6 (IL-6) signaling can lead to activation of the epidermal growth factor receptor (EGFR), which prolongs Stat3 activation. In the present experiments, we tested the hypothesis that IL-6 signaling activates EGFR signaling in peripheral and spinal nociception and examined whether EGFR localization and activation coincide with pain-related behaviors in arthritis. In vivo in anesthetized rats, spinal application of the EGFR receptor blocker gefitinib reduced the responses of spinal cord neurons to noxious joint stimulation, but only after spinal pretreatment with IL-6 and soluble IL-6 receptor. Using Western blots, we found that IL-6-induced Stat3 activation was reduced by gefitinib in microglial cells of the BV2 cell line, but not in cultured DRG neurons. Immunohistochemistry showed EGFR localization in most DRG neurons from normal rats, but significant downregulation in the acute and most painful arthritis phase. In the spinal cord of mice, EGFR was highly activated mainly in the chronic phase of inflammation, with localization in neurons. These data suggest that spinal IL-6 signaling may activate spinal EGFR signaling. Downregulation of EGFR in DRG neurons in acute arthritis may limit nociception, but pronounced delayed activation of EGFR in the spinal cord may be involved in chronic inflammatory pain.