Suppressive effect of simvastatin on interferon-β-induced expression of CC chemokine ligand 5 in microglia
Suppressive effect of simvastatin on interferon-β-induced expression of CC chemokine ligand 5 in microglia
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DOI：
10.1016/j.neulet.2006.08.044
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发表时间：
2006-10-30
影响因子：
2.5
通讯作者：
Kurane, Ichiro
中科院分区：
文献类型：
--
作者：
Nakamichi, Kazuo;Saiki, Megumi;Kurane, Ichiro
尽管小胶质细胞在大脑免疫系统中发挥着关键作用，但越来越多的证据表明，小胶质细胞过度激活会引起神经元和神经胶质损伤，导致神经退行性和神经炎症性疾病。 3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂或他汀类药物最近因其对中枢神经系统炎症的抑制作用而受到广泛关注。在当前的研究中，我们研究了他汀类药物介导的小胶质细胞功能抑制，特别是趋化因子产生的抑制。用干扰素-β (IFN-β) 刺激小胶质细胞导致 CC 趋化因子配体 5 (CCL5) 的表达，CC 趋化因子配体 5 (CCL5) 是炎症细胞的主要趋化因子。 IFN-β 和肿瘤坏死因子-α (TNF-α) 的共刺激可协同增强小胶质细胞 CCL5 反应。辛伐他汀治疗显着减少了单独的 IFN-β 或 IFN-β/TNF-α 组合诱导的小胶质细胞 CCL5 表达。在存在辛伐他汀的情况下，IFN-β 诱导的 Janus 激酶 (Jak) 信号转导子和转录激活子 (STAT) 途径的激活被减弱，尽管该化合物对 TNF-α 诱发的核因子 kappa B 和 c-Jun N 末端激酶途径的激活影响很小或没有影响。此外，Jak-STAT信号传导的化学抑制剂显着减少了小胶质细胞中IFN-β诱导的CCL5表达。综上所述，这些结果表明辛伐他汀通过下调 Jak-STAT 信号通路来抑制 IFN-β 诱导的 CCL5 表达。 (c) 2006 年，爱思唯尔爱尔兰有限公司出版。
Despite the pivotal role of microglia in immune system of the brain, a growing body of evidence suggests that the excessive microglial activation provokes neuronal and glial damages, leading to neurodegenerative and neuroinflammatory disorders. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, have recently received much attention for their suppressive effects on inflammation in the central nervous system. In the current study, we have examined the statin-mediated inhibition of microglial function, especially that of chemokine production. Stimulation of microglial cells with interferon-beta (IFN-beta) resulted in the expression of CC chemokine ligand 5 (CCL5), a major chemoattractant of inflammatory cells. Microglial CCL5 response was synergistically potentiated by costimulation with IFN-beta and tumor necrosis factor-alpha (TNF-alpha). The simvastatin treatment significantly diminished the microglial CCL5 expression induced by IFN-beta alone or by IFN-beta/TNF-alpha combination. In the presence of simvastatin, the IFN-beta-induced activation of Janus kinase (Jak)-signal transducer and activator of transcription (STAT) pathway was attenuated, although this compound had little or no effect on the TNF-alpha-evoked activation of nuclear factor kappa B and c-Jun N-terminal kinase pathways. In addition, chemical inhibitor of Jak-STAT signaling significantly diminished the IFN-beta-induced expression of CCL5 in microglia. Taken together, these results suggest that simvastatin suppresses the IFN-beta-induced expression of CCL5 via down-regulation of Jak-STAT signaling pathway. (c) 2006 Published by Elsevier Ireland Ltd.