Kang M K, Kang S K
Department of Physiology, College of Medicine, Pusan National University, Ami-Dong, Seo-Gu, Busan, South Korea.
Cell Prolif. 2008 Jun;41(3):377-92. doi: 10.1111/j.1365-2184.2008.00537.x.
In a previous study, we observed cell proliferation 3 days after spinal cord injury, and levels of interleukin-6 (IL-6) and epidermal growth factor (EGF) had significantly increased in the region of the injury.
The purpose of the new study described here was to evaluate the roles of IL-6 and EGF after traumatic damage to the spinal cord having isolated neural progenitor cells (NPC) from adult mice.
Evidence provided by the trypan blue dye exclusion assay, 5-bromodeoxyuridine immunoreactivity and Western blot analysis indicated that IL-6 and EGF induced proliferation of these spinal cord-derived NPCs via phosphorylation of Janus-activated kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinases (MAPK), respectively. Combined treatment with IL-6 and EGF accelerated proliferation of cells synergistically and phosphorylation of STAT3 and extracellular signal-regulated kinase 1/2 (Erk1/2). Furthermore, AG490 and AG1478, JAK2 inhibitor and EGFR inhibitor, respectively, prevented the IL-6- and EGF-induced proliferation of the cells. Interestingly, IL-6-activated MAPKs but EGF did not influence JAK2/STAT3 activation; AG490 specifically inhibited IL-6-induced Erk1/2 phosphorylation without affecting IL-6-induced phosphorylation of Raf and MEK1/2. These results indicate that IL-6 is directly involved in Erk1/2 activation via JAK2 and that Erk1/2 provides a signal bridge between the IL-6-induced JAK2/STAT3 pathway and EGF-induced MAPK pathway.
Our study is the first demonstration of IL-6- and EGF-stimulated proliferation of spinal cord progenitor cells via JAK2/STAT3 and MAPK signalling pathways. These pathways play key roles in repopulation and regeneration of spinal cord tissue after injury. It may represent novel therapeutic targets for pharmacological intervention in central nervous system disease, including spinal cord injury.
在之前的一项研究中，我们观察到脊髓损伤3天后的细胞增殖情况，并且损伤区域白细胞介素-6（IL-6）和表皮生长因子（EGF）的水平显著升高。
本文所述新研究的目的是在从成年小鼠中分离出神经祖细胞（NPC）后，评估IL-6和EGF在脊髓创伤性损伤后的作用。
台盼蓝染料排除试验、5-溴脱氧尿苷免疫反应性和蛋白质免疫印迹分析提供的证据表明，IL-6和EGF分别通过Janus激活激酶2（JAK2）/信号转导子和转录激活子3（STAT3）的磷酸化以及丝裂原活化蛋白激酶（MAPK）诱导这些脊髓来源的NPC增殖。IL-6和EGF联合处理协同加速细胞增殖以及STAT3和细胞外信号调节激酶1/2（Erk1/2）的磷酸化。此外，JAK2抑制剂AG490和表皮生长因子受体（EGFR）抑制剂AG1478分别阻止了IL-6和EGF诱导的细胞增殖。有趣的是，IL-6激活MAPK，但EGF不影响JAK2/STAT3激活；AG490特异性抑制IL-6诱导的Erk1/2磷酸化，而不影响IL-6诱导的Raf和MEK1/2磷酸化。这些结果表明，IL-6通过JAK2直接参与Erk1/2激活，并且Erk1/2在IL-6诱导的JAK2/STAT3途径和EGF诱导的MAPK途径之间提供信号桥梁。
我们的研究首次证明了IL-6和EGF通过JAK2/STAT3和MAPK信号通路刺激脊髓祖细胞增殖。这些通路在损伤后脊髓组织的细胞重新填充和再生中起关键作用。它可能代表了对包括脊髓损伤在内的中枢神经系统疾病进行药物干预的新治疗靶点。
