Peroxisome-proliferator-activated receptors γ and peroxisome-proliferator-activated receptors β/δ and the regulation of interleukin 1 receptor antagonist expression by pioglitazone in ischaemic brain
Peroxisome-proliferator-activated receptors γ and peroxisome-proliferator-activated receptors β/δ and the regulation of interleukin 1 receptor antagonist expression by pioglitazone in ischaemic brain
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DOI：
10.1097/hjh.0b013e3283396e4e
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发表时间：
2010-07-01
影响因子：
4.9
通讯作者：
Zhao, Yi
中科院分区：
文献类型：
--
作者：
Glatz, Torben;Stoeck, Ivonne;Zhao, Yi
目的缺血性脑中白细胞介素-1 （IL-1）配体、IL-1 α、IL-1 β和IL-1受体拮抗剂（IL-1ra）的分泌和释放失衡，可加重炎症反应，导致神经元死亡。脑缺血也上调过氧化物酶体增殖物激活受体(PPAR) γ。我们研究了PPAR γ激动剂吡格列酮对大脑中动脉闭塞90 min后缺血脑内IL-1 β、IL-1ra和IL-1受体I （IL-1RI）表达的调节作用。方法在大脑中动脉闭塞前、闭塞中、闭塞后24、48 h分别给予吡格列酮或对照物脑室灌注。采用免疫组化、免疫印迹、免疫荧光染色等方法检测梗死周围皮层中IL-1 β、IL-1ra、IL-1RI的表达。在表达PPAR γ和PPAR β / δ的初代皮质神经元中，研究了吡格列酮对IL-1ra的调节机制和兴奋性神经损伤下的神经保护作用。结果脑缺血使缺血皮质中IL-1 β、IL-1RI和IL-1ra的表达升高。吡格列酮降低IL-1 β，但上调IL-1ra，增加IL-1ra免疫反应细胞的数量。在初级皮质神经元中，吡格列酮通过激活PPAR β / δ刺激IL-1ra的产生，但通过PPAR γ依赖机制防止兴奋性毒性神经元损伤和死亡。结论proglitazone在神经元中激活PPAR γ和PPAR β / δ可触发多种神经保护机制。缺血脑组织中I1-1 β和IL-1ra之间平衡的恢复限制了IL-1 β信号传导，减少了炎症反应，是噻唑烷二酮类药物改善缺血性卒中恢复的重要机制。[J] .中华医学杂志，2010,28 (3):388 - 397 (C)。
Objective The imbalance between the production and release of interleukin-1 (IL-1) ligands, IL-1 alpha, IL-1 beta and IL-1 receptor antagonist (IL-1ra) in ischaemic brain exaggerates inflammatory responses and contributes to neuronal death. Cerebral ischaemia also upregulates the peroxisome-proliferator-activated receptor (PPAR) gamma. We studied in rats the effects of the PPAR gamma agonist, pioglitazone, on the regulation of IL-1 beta, IL-1ra and IL-1 receptor I (IL-1RI) expression in ischaemic brain after occlusion of the middle cerebral artery for 90 min.Methods Pioglitazone or vehicle was infused intracerebroventricularly over a 5-day period before, during and 24 or 48 h after middle cerebral artery occlusion. The expression of IL-1 beta, IL-1ra and IL-1RI in the peri-infarct cortex was investigated by immunohistochemistry, Western blotting and immunofluorescence staining. The mechanisms of the IL-1ra regulation by pioglitazone and the neuroprotection under excitotoxic neuronal injury were studied in primary cortical neurones expressing PPAR gamma and PPAR beta/delta.Results Cerebral ischaemia increased the expression of IL-1 beta, IL-1RI and IL-1ra in the ischaemic cortex. Pioglitazone reduced IL-1 beta, but upregulated IL-1ra and increased the number of IL-1ra immunoreactive cells. In primary cortical neurones, pioglitazone stimulated the IL-1ra production via activation of the PPAR beta/delta, but prevented excitotoxic neuronal injury and death by a PPAR gamma-dependent mechanism.Conclusion Our data demonstrate that activation of PPAR gamma and PPAR beta/delta by proglitazone in neurones triggers diverse neuroprotective mechanisms. The restoration of the equilibrium between I1-1 beta and IL-1ra in ischaemic brain tissue limits IL-1 beta signalling, reduces inflammatory responses and is an important mechanism by which thiazolidinediones improve the recovery from ischaemic stroke. J Hypertens 28:1488-1497 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.