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Abstract：
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.
摘要：
在肿瘤细胞中，白细胞介素-6（IL-6）信号可以导致表皮生长因子受体（EGFR）的激活，延长Stat3激活。在目前的实验中,我们检验了IL-6信号在外周和脊髓伤害性感受中激活EGFR信号的假设,并检查了EGFR定位和激活是否与关节炎的疼痛相关行为一致.在麻醉大鼠体内，EGFR受体阻滞剂吉非替尼的脊髓应用降低了脊髓神经元对有害关节刺激的反应，但仅在用IL-6和可溶性IL-6受体进行脊髓预处理后。使用西方印迹，我们发现，IL-6诱导的Stat3激活被吉非替尼在BV2细胞系的小胶质细胞中降低，但不是在培养的DRG神经元中。免疫组化显示EGFR在大多数正常大鼠的DRG神经元中定位，但在急性和最痛苦的关节炎阶段显著下调。在小鼠的脊髓中，EGFR主要在炎症的慢性期高度激活，在神经元中定位。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EGFR的下调可能会限制伤害感受，但脊髓EGFR明显延迟激活可能与慢性炎性疼痛有关.
