Department of Neurology, Charité– Universitätsmedizin Berlin, 10117 Berlin, Germany.
Brain. 2012 Jun;135(Pt 6):1964-80. doi: 10.1093/brain/aws075. Epub 2012 Apr 3.
Ambivalent effects of interleukin-6 on the pathogenesis of ischaemic stroke have been reported. However, to date, the long-term actions of interleukin-6 after stroke have not been investigated. Here, we subjected interleukin-6 knockout (IL-6(-/-)) and wild-type control mice to mild brain ischaemia by 30-min filamentous middle cerebral artery occlusion/reperfusion. While ischaemic tissue damage was comparable at early time points, IL-6(-/-) mice showed significantly increased chronic lesion volumes as well as worse long-term functional outcome. In particular, IL-6(-/-) mice displayed an impaired angiogenic response to brain ischaemia with reduced numbers of newly generated endothelial cells and decreased density of perfused microvessels along with lower absolute regional cerebral blood flow and reduced vessel responsivity in ischaemic striatum at 4 weeks. Similarly, the early genomic activation of angiogenesis-related gene networks was strongly reduced and the ischaemia-induced signal transducer and activator of transcription 3 activation observed in wild-type mice was almost absent in IL-6(-/-) mice. In addition, systemic neoangiogenesis was impaired in IL-6(-/-) mice. Transplantation of interleukin-6 competent bone marrow into IL-6(-/-) mice (IL-6(chi)) did not rescue interleukin-6 messenger RNA expression or the early transcriptional activation of angiogenesis after stroke. Accordingly, chronic stroke outcome in IL-6(chi) mice recapitulated the major effects of interleukin-6 deficiency on post-stroke regeneration with significantly enhanced lesion volumes and reduced vessel densities. Additional in vitro experiments yielded complementary evidence, which showed that after stroke resident brain cells serve as the major source of interleukin-6 in a self-amplifying network. Treatment of primary cortical neurons, mixed glial cultures or immortalized brain endothelia with interleukin 6-induced robust interleukin-6 messenger RNA transcription in each case, whereas oxygen-glucose deprivation did not. However, oxygen-glucose deprivation of organotypic brain slices resulted in strong upregulation of interleukin-6 messenger RNA along with increased transcription of key angiogenesis-associated genes. In conclusion, interleukin-6 produced locally by resident brain cells promotes post-stroke angiogenesis and thereby affords long-term histological and functional protection.
已有报道称白细胞介素-6（IL-6）对缺血性中风的发病机制具有双重作用。然而，迄今为止，中风后白细胞介素-6的长期作用尚未得到研究。在这里，我们通过 30 分钟的线栓法大脑中动脉闭塞/再灌注，使白细胞介素-6 敲除（IL-6(-/-)) 和野生型对照小鼠发生轻度脑缺血。虽然在早期缺血组织损伤相当，但 IL-6(-/-) 小鼠显示出明显更大的慢性病灶体积以及更差的长期功能结果。具体而言，IL-6(-/-) 小鼠表现出对脑缺血的血管生成反应受损，新生内皮细胞数量减少，灌注微血管密度降低，同时缺血纹状体的绝对区域性脑血流减少，血管反应性降低，4 周时。同样，血管生成相关基因网络的早期基因组激活也大大降低，而在野生型小鼠中观察到的缺血诱导的信号转导和转录激活 3（STAT3）激活几乎不存在于 IL-6(-/-) 小鼠中。此外，IL-6(-/-) 小鼠的全身新生血管形成受损。将白细胞介素-6 有功能的骨髓移植到 IL-6(-/-) 小鼠（IL-6(chi)) 中并没有挽救中风后白细胞介素-6 mRNA 表达或血管生成的早期转录激活。因此，IL-6(chi) 小鼠的慢性中风结果再现了白细胞介素-6 缺乏对中风后再生的主要影响，表现为病灶体积明显增大和血管密度降低。额外的体外实验提供了补充证据，表明中风后，驻留脑细胞是自我放大网络中白细胞介素-6 的主要来源。用白细胞介素 6 处理原代皮质神经元、混合神经胶质培养物或永生化脑内皮细胞，在每种情况下均诱导强烈的白细胞介素-6 mRNA 转录，而缺氧-葡萄糖剥夺则没有。然而，器官型脑片的缺氧-葡萄糖剥夺导致白细胞介素-6 mRNA 的强烈上调，以及关键血管生成相关基因的转录增加。总之，由驻留脑细胞局部产生的白细胞介素-6 促进了中风后的血管生成，从而提供了长期的组织学和功能保护。
