Department of Clinical Science and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Brain Res. 2013 Jun 23;1517:122-32. doi: 10.1016/j.brainres.2013.04.022. Epub 2013 Apr 18.
Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES) is a well-known pro-inflammatory chemokine and its role in ischemic stroke remains controversial. We examined the significance of RANTES in ischemic stroke and aimed to elucidate the direct effect of RANTES on neurons. Plasma concentrations of major C-C chemokines, including RANTES, and neurotrophic factors were examined in 171 ischemic stroke patients and age- and gender- matched healthy subjects. Plasma concentrations of RANTES at day 0 after onset were significantly elevated in stroke patients, compared with controls, and were highly correlated with those of BDNF, EGF, and VEGF. In a mouse middle cerebral artery occlusion model (MCAO), plasma RANTES was significantly elevated and the expression of RANTES was markedly upregulated in neurons particularly in peri-infarct areas. The expression of CCR3 and CCR5, receptors for RANTES, was also induced in neurons, while another receptor, CCR1, was observed in vascular cells, in peri-infarct areas after MCAO. We examined the effects of RANTES on differentiated PC12 cells, a model of neuronal cells. Treatment with RANTES induced the activation of Akt and Erk1/2, and attenuated the cleavage of caspase-3 in the cells. RANTES increased the expression of BDNF, EGF, and VEGF in the cells. Moreover, RANTES maintained the number of cells under serum free conditions. The RANTES-mediated upregulation of neurotrophic factors and cell survival were significantly attenuated by the inhibition of Akt or Erk1/2. Taken together, RANTES is an interesting chemokine that is produced from neurons after ischemic stroke and has the potential to protect neurons directly or indirectly through the production of neurotrophic factors in peri-infarct areas.
调节激活正常 T 细胞表达和分泌（RANTES）是一种众所周知的促炎趋化因子，其在缺血性中风中的作用仍存在争议。我们研究了 RANTES 在缺血性中风中的意义，并旨在阐明 RANTES 对神经元的直接作用。在 171 例缺血性中风患者和年龄及性别匹配的健康对照者中，检测了主要 C-C 趋化因子（包括 RANTES）和神经营养因子的血浆浓度。与对照组相比，中风患者发病后第 0 天的 RANTES 血浆浓度明显升高，且与 BDNF、EGF 和 VEGF 的浓度高度相关。在小鼠大脑中动脉闭塞模型（MCAO）中，血浆 RANTES 明显升高，神经元中特别是梗死周围区 RANTES 的表达明显上调。神经元中 CCR3 和 CCR5 的表达也被诱导，而另一个受体 CCR1 则在 MCAO 后梗死周围区的血管细胞中观察到。我们研究了 RANTES 对分化的 PC12 细胞（神经元细胞模型）的影响。RANTES 处理诱导 Akt 和 Erk1/2 的激活，并减弱细胞中 caspase-3 的裂解。RANTES 增加了细胞中 BDNF、EGF 和 VEGF 的表达。此外，RANTES 在无血清条件下维持细胞数量。RANTES 介导的神经营养因子上调和细胞存活作用，通过 Akt 或 Erk1/2 的抑制而显著减弱。总之，RANTES 是一种有趣的趋化因子，它在缺血性中风后由神经元产生，具有通过在梗死周围区产生神经营养因子直接或间接保护神经元的潜力。
