Peroxisome-proliferator-activated receptor gamma (PPARγ) is required for modulating endothelial inflammatory response through a nongenomic mechanism
Peroxisome-proliferator-activated receptor gamma (PPARγ) is required for modulating endothelial inflammatory response through a nongenomic mechanism
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DOI：
10.1016/j.ejcb.2010.04.002
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发表时间：
2010-09-01
影响因子：
6.6
通讯作者：
Luconi, Michaela
中科院分区：
文献类型：
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作者：
Cantini, Giulia;Lombardi, Adriana;Luconi, Michaela
除了众所周知的抗糖尿病作用外，过氧化物酶体增殖物激活受体γ(PPARγ)噻唑烷二酮配体(TZD)也被认为具有抗炎特性。受体在调节这种效应中的作用还远未阐明。在这里，我们证明了PPAR-γ是TZD干扰人内皮细胞中肿瘤坏死因子-α和干扰素-γ炎症活动所必需的。不同的PPARγ配体类似地以剂量依赖的方式抑制干扰素γ诱导的10 kDa蛋白(IP10)分泌的细胞质刺激，并阻止诱导的细胞外信号调节激酶(ERK1/2)的磷酸化/激活。为了进一步证实PPARγ在介导其配体的快速和长期抗炎作用中的作用，我们在PPARγ沉默和过度表达的细胞中评估了RGZ的抑制作用。PPARγ沉默导致RGZ对细胞/趋化因子分泌的抑制活性逆转，并导致ERK快速磷酸化。相反，受体过表达显著增加RGZ抑制活性。终于来了。即使在没有RGZ的情况下，PPARγ过表达也导致ERK1/2的磷酸化和炎症分泌减少，这表明了内源性配体控制的抑制作用。综上所述，我们的研究结果首次证明PPARγ参与了TZD对内皮细胞的抗炎作用，不仅通过调节细胞/趋化因子的分泌，而且通过一种新的快速非基因组机制抑制ERK的激活。(C)2010年爱思唯尔股份有限公司。版权所有。
Besides their well-known anti-diabetic effects, the peroxisome-proliferator-activated receptor gamma (PPAR gamma) thiazolidinedione ligands (TZD) have been suggested to also display anti-inflammatory properties. The receptor role in mediating such effects is far from being elucidated. Here, we demonstrated that PPAR gamma is necessary for TZD to interfere with TNF alpha and IFN gamma inflammatory activity in human endothelial cells. Different PPAR gamma ligands similarly inhibit cytokinic stimulation of IFN gamma-inducible-protein-of-10-kDa (IP10) secretion in a dose-dependent manner and prevent the induced phosphorylation/activation of extracellular-signaling-regulated-kinases (ERK1/2). To further confirm the PPAR gamma role in mediating both rapid and long term anti-inflammatory effects of its ligands, we evaluated RGZ inhibitory action in PPAR gamma-silenced and -overexpressing cells. PPAR gamma-silencing results in a reversion of RGZ inhibitory activity on cyto/chemokine secretions and rapid ERK phosphorylation. Conversely, receptor overexpression significantly increases RGZ inhibitory activity. Finally. PPAR gamma-overexpression results in a reduction of ERK1/2 phosphorylation and inflammatory secretions in response to TNF alpha and IFN gamma even in the absence of RGZ, suggesting a restraining effect controlled by endogenous ligands.In conclusion, our data provide the first evidence that PPAR gamma is involved in the anti-inflammatory action of TZD in endothelial cells, not only by modulating cyto/chemokine secretions but also by restraining ERK activation through a novel rapid nongenomic mechanism. (C) 2010 Elsevier GmbH. All rights reserved.