Gemfibrozil, a lipid-lowering drug, upregulates IL-1 receptor antagonist in mouse cortical neurons: implications for neuronal self-defense.
Gemfibrozil, a lipid-lowering drug, upregulates IL-1 receptor antagonist in mouse cortical neurons: implications for neuronal self-defense.
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DOI：
10.4049/jimmunol.1102624
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发表时间：
2012-07-15
期刊：
影响因子：
--
通讯作者：
Pahan K
中科院分区：
文献类型：
--
作者：
Corbett GT;Roy A;Pahan K
慢性炎症正在成为多种神经退行性疾病的标志，因此，促炎症细胞因子白介素1β(IL-1β)参与了神经退行性疾病的发病机制。IL-1β与其高亲和力受体--白介素1受体(IL-1R)结合并上调促炎信号通路，而白介素1受体拮抗剂(IL-1ra)则与同一受体结合并抑制促炎细胞信号转导。因此，上调IL-1ra被认为在减轻炎症方面具有重要意义。本研究强调了FDA批准的降脂药物吉非罗齐在增加原代小鼠和人类神经元IL-1ra表达方面的新应用。吉非罗齐单独作用可使原代培养的小鼠皮质神经元IL-1ra表达明显增加。吉非罗齐激活IA型p110α磷脂酰肌醇3-激酶(PI3-K)和Akt，并用PI3-K和Akt抑制剂阻断吉非罗齐诱导的IL-1ra上调，提示PI3-K-Akt途径在IL-1ra上调中起作用。吉非罗齐还通过PI3-K-Akt途径诱导cAMP反应元件结合(CREB)激活，CREB的siRNA减弱可阻断吉非罗齐介导的IL-1ra增加。此外，吉非罗齐还能保护神经元免受IL-1β损伤。然而，抑制神经元IL-1ra的小干扰RNA阻断了吉非罗齐对IL-1β的保护作用，提示吉非罗齐通过上调IL-1ra来增强皮层神经元的防御机制。综上所述，这些结果强调了PI3-K-Akt-CREB通路在介导吉非罗齐诱导的神经元IL-1ra上调中的重要性，并提示吉非罗齐可能是一种在神经炎性和神经退行性疾病中传播神经元自我防御的治疗方法。
Chronic inflammation is becoming a hallmark of several neurodegenerative disorders and accordingly, interleukin-1 beta (IL-1β), a proinflammatory cytokine, is implicated in the pathogenesis of neurodegenerative diseases. While IL-1β binds to its high-affinity receptor, interleukin-1 receptor (IL-1R), and upregulates proinflammatory signaling pathways, interleukin-1 receptor antagonist (IL-1Ra) adheres to the same receptor and inhibits proinflammatory cell signaling. Therefore, upregulation of IL-1Ra is considered important in attenuating inflammation. The present study underlines a novel application of gemfibrozil, an FDA-approved lipid-lowering drug, in increasing the expression of IL-1Ra in primary mouse and human neurons. Gemfibrozil alone induced an early and pronounced increase in the expression of IL-1Ra in primary mouse cortical neurons. Activation of type IA p110α phosphatidylinositol 3-kinase (PI3-K) and Akt by gemfibrozil and abrogation of gemfibrozil-induced upregulation of IL-1Ra by inhibitors of PI3-K and Akt indicate a role of the PI3-K – Akt pathway in the upregulation of IL-1Ra. Gemfibrozil also induced the activation of cAMP response element-binding (CREB) via the PI3-K – Akt pathway and siRNA attenuation of CREB abolished the gemfibrozil-mediated increase in IL-1Ra. Furthermore, gemfibrozil was able to protect neurons from IL-1β insult. However, siRNA knockdown of neuronal IL-1Ra abrogated the protective effect of gemfibrozil against IL-1β suggesting that this drug increases the defense mechanism of cortical neurons via upregulation of IL-1Ra. Together, these results highlight the importance of the PI3-K – Akt – CREB pathway in mediating gemfibrozil-induced upregulation of IL-1Ra in neurons and suggest gemfibrozil as a possible therapeutic treatment for propagating neuronal self defense in neuroinflammatory and neurodegenerative disorders.
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DOI：
10.1523/jneurosci.1243-10.2010
发表时间：
2010-09-22
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Jana A;Pahan K
通讯作者：
Pahan K
影响因子：
56.9
作者：
Franke, TF;Kaplan, DR;Toker, A
通讯作者：
Toker, A
影响因子：
9.3
作者：
Griffin, W. Sue T.;Liu, Ling;Barger, Steven W.
通讯作者：
Barger, Steven W.
影响因子：
4.8
作者：
Jana, A;Pahan, K
通讯作者：
Pahan, K
DOI：
10.1523/jneurosci.4144-09.2009
发表时间：
2009-10-28
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Ghosh A;Roy A;Matras J;Brahmachari S;Gendelman HE;Pahan K
通讯作者：
Pahan K