Poly(ADP-ribose) polymerase-1 activity promotes NF-κB-driven transcription and microglial activation:: implication for neurodegenerative disorders
Poly(ADP-ribose) polymerase-1 activity promotes NF-κB-driven transcription and microglial activation:: implication for neurodegenerative disorders
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DOI：
10.1046/j.1471-4159.2003.01684.x
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发表时间：
2003-04-01
影响因子：
4.7
通讯作者：
Moskowitz, MA
中科院分区：
文献类型：
--
作者：
Chiarugi, A;Moskowitz, MA
激活的胶质细胞过度释放促炎产物导致神经毒性并参与神经退行性疾病的发病机制。最近，聚（adp -核糖）聚合酶-1 （PARP-1）被证明在神经免疫反应中核因子κ B （nf - κ B）驱动的炎症介质表达中发挥关键作用。在这里，我们报告了一项新的发现，PARP-1的酶活性以β -烟酰胺腺嘌呤二核苷酸依赖的方式促进了暴露于脂多糖、干扰素或β -淀粉样蛋白1-40的小胶质细胞中NF-kappaB的DNA结合。与此一致的是，我们发现用PARP-1酶活性的药理抑制剂靶向nf - kappab依赖性胶质细胞激活可降低炎症介质的表达，如诱导型一氧化氮合酶、白细胞介素1 β、肿瘤坏死因子α和淀粉样蛋白前体蛋白，并降低体外活化胶质细胞的神经毒性潜能。重要的是，体内脂多糖诱导的聚（adp -核糖）形成的药理抑制可抑制神经炎症和相关的神经细胞死亡。我们的研究结果建立在先前发表的PARP-1缺失小鼠报告的基础上，强调了PARP-1酶活性在神经胶质激活过程中转录控制的重要性，确定了PARP-1活性依赖性调节NF-kappaB作为急性和慢性神经退行性疾病治疗干预的新药理学靶点。
Excessive release of proinflammatory products by activated glia causes neurotoxicity and participates in the pathogenesis of neurodegenerative disorders. Recently, poly(ADP-ribose) polymerase-1 (PARP-1) has been shown to play a key role in nuclear factor kappa B (NF-kappaB)-driven expression of inflammatory mediators by glia during the neuroimmune response. Here we report the novel finding that the enzymatic activity of PARP-1 promotes, in an beta-nicotinamide adenine dinucleotide-dependent fashion, the DNA binding of NF-kappaB in microglia exposed to lipopolysaccharides, interferon-gamma or beta-amyloid 1-40. Consistently, we found that targeting NF-kappaB-dependent glial activation with pharmacological inhibitors of PARP-1 enzymatic activity reduces expression of inflammatory mediators such as inducible nitric oxide synthase, interleukin 1beta, tumor necrosis factor alpha and amyloid precursor protein, and reduces the neurotoxic potential of activated glia in vitro . Importantly, pharmacological inhibition of lipopolysaccharide-induced poly(ADP-ribose) formation in vivo suppresses neuroinflammation and related neural cell death. Our findings build on prior published reports in PARP-1 null mice and highlight the importance of PARP-1 enzymatic activity in transcriptional control during glial activation, identifying PARP-1 activity-dependent regulation of NF-kappaB as a novel pharmacological target for therapeutic intervention in the treatment of acute and chronic neurodegenerative disorders.