内源性大麻素 2-花生四烯酸甘油抑制 COX-2 的表达是通过 PPAR-γ 介导的。
Inhibition of COX-2 expression by endocannabinoid 2-arachidonoylglycerol is mediated via PPAR-γ.
机构信息
Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA.
出版信息
Br J Pharmacol. 2011 Aug;163(7):1533-49. doi: 10.1111/j.1476-5381.2011.01444.x.
BACKGROUND AND PURPOSE
Endocannabinoids have both anti-inflammatory and neuroprotective properties against harmful stimuli. We previously demonstrated that the endocannabinoid 2-arachidonoylglycerol (2-AG) protects hippocampal neurons by limiting the inflammatory response via a CB(1) receptor-dependent MAPK/NF-κB signalling pathway. The purpose of the present study was to determine whether PPARγ, an important nuclear receptor, mediates 2-AG-induced inhibition of NF-κB phosphorylation and COX-2 expression, and COX-2-enhanced miniature spontaneous excitatory postsynaptic currents (mEPSCs).
EXPERIMENTAL APPROACH
By using a whole-cell patch clamp electrophysiological recording technique and immunoblot analysis, we determined mEPSCs, expression of COX-2 and PPARγ, and phosphorylation of NF-kB in mouse hippocampal neurons in culture.
KEY RESULTS
Exogenous and endogenous 2-AG-produced suppressions of NF-κB-p65 phosphorylation, COX-2 expression and excitatory synaptic transmission in response to pro-inflammatory interleukin-1β (IL-1β) and LPS were inhibited by GW9662, a selective PPARγ antagonist, in hippocampal neurons in culture. PPARγ agonists 15-deoxy-Δ(12,14) -prostaglandin J(2) (15d-PGJ(2)) and rosiglitazone mimicked the effects of 2-AG on NF-κB-p65 phosphorylation, COX-2 expression and mEPSCs, and these effects were eliminated by antagonism of PPARγ. Moreover, exogenous application of 2-AG or elevation of endogenous 2-AG by inhibiting its hydrolysis with URB602 or JZL184, selective inhibitors of monoacylglycerol lipase (MAGL), prevented the IL-1β- and LPS-induced reduction of PPARγ expression. The 2-AG restoration of the reduced PPARγ expression was blocked or attenuated by pharmacological or genetic inhibition of the CB(1) receptor.
CONCLUSIONS AND IMPLICATIONS
Our results suggest that CB(1) receptor-dependent PPARγ expression is an important and novel signalling pathway in endocannabinoid 2-AG-produced resolution of neuroinflammation in response to pro-inflammatory insults.
背景与目的
内源性大麻素具有抗炎和神经保护作用，可对抗有害刺激。我们之前的研究表明，内源性大麻素 2-花生四烯酸甘油（2-AG）通过 CB1 受体依赖性 MAPK/NF-κB 信号通路限制炎症反应，从而保护海马神经元。本研究旨在确定核受体 PPARγ 是否介导 2-AG 诱导的 NF-κB 磷酸化和 COX-2 表达抑制以及 COX-2 增强的微小自发性兴奋性突触后电流（mEPSC）。
实验方法
通过全细胞膜片钳电生理记录技术和免疫印迹分析，我们在培养的小鼠海马神经元中测定 mEPSC、COX-2 和 PPARγ 的表达以及 NF-κB 的磷酸化。
主要结果
外源性和内源性 2-AG 对炎性细胞因子白细胞介素-1β（IL-1β）和 LPS 反应产生的 NF-κB-p65 磷酸化、COX-2 表达和兴奋性突触传递的抑制作用，可被选择性 PPARγ 拮抗剂 GW9662 抑制。在培养的海马神经元中，PPARγ 激动剂 15-脱氧-Δ（12,14）-前列腺素 J2（15d-PGJ2）和罗格列酮模拟了 2-AG 对 NF-κB-p65 磷酸化、COX-2 表达和 mEPSC 的作用，这些作用被 PPARγ 拮抗剂消除。此外，外源性应用 2-AG 或通过抑制其水解用 URB602 或 JZL184（单酰基甘油脂肪酶（MAGL）的选择性抑制剂）升高内源性 2-AG，可防止 IL-1β 和 LPS 诱导的 PPARγ 表达降低。2-AG 恢复降低的 PPARγ 表达被 CB1 受体的药理学或遗传学抑制阻断或减弱。
结论与意义
我们的结果表明，CB1 受体依赖性 PPARγ 表达是内源性大麻素 2-AG 产生的神经炎症反应消退的重要且新颖的信号通路，可对抗炎症刺激。
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