Peroxisome proliferator-activated receptorsγ (PPARγ) differently modulate the interleukin-6 expression in the peri-infarct cortical tissue in the acute and delayed phases of cerebral ischaemia
Peroxisome proliferator-activated receptorsγ (PPARγ) differently modulate the interleukin-6 expression in the peri-infarct cortical tissue in the acute and delayed phases of cerebral ischaemia
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DOI：
10.1111/j.1460-9568.2008.06478.x
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发表时间：
2008-11-01
影响因子：
3.4
通讯作者：
Culman, Juraj
中科院分区：
文献类型：
--
作者：
Patzer, Andreas;Zhao, Yi;Culman, Juraj
白细胞介素-6（IL-6）在脑缺血后发挥神经保护作用，但也可加重炎症并诱导神经元死亡。本研究探讨了脑过氧化物酶体增殖物激活受体γ（PPAR γ）在局灶性脑缺血大鼠梗死周围皮质组织IL-6表达调节中的作用。吡格列酮，一种高亲和力的过氧化物酶体增殖体激活受体γ配体，脑室内（i. c. v.）在大脑中动脉闭塞（MCAO）90 min后再灌注之前、期间和之后24 h或48 h内通过渗透压微型泵在5 d内进行。在MCAO后24 h和48 h研究了邻近缺血核心的皮质组织中的PPAR γ和IL-6的表达。吡格列酮在两个时间点均增强了缺血诱导的PPAR γ上调。脑缺血实质上增加了梗死周围皮质组织中的IL-6表达。MCAO后24小时，大多数小胶质细胞/巨噬细胞显示出强烈的IL-6免疫反应性。IL-6也定位于神经元中，但梗死边缘IL-6阳性染色的神经元分布非常不均匀。吡格列酮可有效降低MCAO后24 h的IL-6免疫反应细胞数量和IL-6蛋白水平，但在48 h时则无此作用。吡格列酮治疗可缩小梗死面积，改善神经功能。目前的研究表明，大脑过氧化物酶体增殖物激活受体γ抑制缺血性脑组织中的IL-6的表达在缺血性中风的初始阶段，其中IL-6的过度产生可能会加重神经元损伤，但不是在以后的时间点，当IL-6促进神经保护和抑制神经元死亡。
Interleukin-6 (IL-6) exerts neuroprotective effects after cerebral ischaemia but can also exacerbate inflammation and induce neuronal death. The current study investigates the role of cerebral peroxisome proliferator-activated receptor(s) gamma (PPAR gamma) in the regulation of IL-6 expression in the peri-infarct cortical tissue in rats exposed to focal cerebral ischaemia. Pioglitazone, a high-affinity PPAR gamma ligand, was infused intracerebroventricularly (i.c.v.) via osmotic minipumps over a 5-day period before, during and 24 h or 48 h after middle cerebral artery occlusion (MCAO) for 90 min followed by reperfusion. The expression of PPAR gamma and IL-6 in cortical tissue adjacent to the ischaemic core was studied 24 h and 48 h after MCAO. Pioglitazone augmented the ischaemia-induced upregulation of PPAR gamma at both time points. Cerebral ischaemia substantially increased IL-6 expression in the peri-infarct cortical tissue. Twenty-four hours after MCAO, the majority of microglial cells/macrophages showed an intense IL-6 immunoreactivity. IL-6 was also localized in neurons, but the distribution of neurons positively stained for IL-6 at the border of the infarct was very heterogeneous. Pioglitazone effectively decreased the number of IL-6-immunoreactive cells and IL-6 protein levels at 24 h but not at 48 h after MCAO. Pioglitazone treatment reduced the infarct size and improved neurological functions. The present study demonstrates that cerebral PPAR gamma suppresses the expression of IL-6 in ischaemic brain tissue during the initial phase of ischaemic stroke, in which the overproduction of IL-6 may aggravate neuronal damage, but not at later time points, when IL-6 promotes neuroprotection and inhibits neuronal death.