High mobility group box I protein is released by neural cells upon different stresses and worsens ischemic neurodegeneration in vitro and in vivo
High mobility group box I protein is released by neural cells upon different stresses and worsens ischemic neurodegeneration in vitro and in vivo
复制标题
DOI：
10.1111/j.1471-4159.2007.04788.x
复制
发表时间：
2007-10-01
影响因子：
4.7
通讯作者：
Chiarugi, A.
中科院分区：
文献类型：
--
作者：
Faraco, G.;Fossati, S.;Chiarugi, A.
高迁移率族蛋白是一种染色质结合因子，在维持细胞核稳态中起着重要作用。有证据表明，细胞外释放的高迁移率族蛋白1（HMGB 1）蛋白作为细胞因子，促进炎症并参与外周器官中的多种疾病的发病机制。在这项研究中，我们研究了HMGB 1在神经细胞中的表达水平和迁移动力学，以及其神经病理学潜力。我们报告说，HMGB 1被释放在培养基中的神经元和星形胶质细胞的挑战与坏死，但不是凋亡刺激。重组HMGB 1促进促炎介质如诱导型一氧化氮合酶（NOS）、环氧合酶-2、白细胞介素-1 β和肿瘤坏死因子α的诱导，并在体外增加兴奋性毒性以及缺血性神经元死亡。地塞米松减少HMGB 1依赖性免疫胶质细胞活化，对蛋白质的神经毒性作用没有影响。HMGB 1在小鼠脑的神经元和星形胶质细胞的细胞核中表达，并迅速（1小时）易位到缺血脑内的神经元的细胞质中。脑内微量注射HMGB 1可增加促炎介质的转录水平，并使组织对缺血损伤敏感。总之，数据强调了核HMGB 1的神经病理学作用，并指出该蛋白质是缺血后脑损伤的介质。
High mobility group proteins are chromatin binding factors with key roles in maintenance of nuclear homeostasis. The evidence indicates that extracellularly released high mobility group box 1 (HMGB1) protein behaves as a cytokine, promoting inflammation and participating to the pathogenesis of several disorders in peripheral organs. In this study, we have investigated the expression levels and relocation dynamics of HMGB1 in neural cells, as well as its neuropathological potential. We report that HMGB1 is released in the culture media of neurons and astrocytes challenged with necrotic but not apoptotic stimuli. Recombinant HMGB1 prompts induction of pro-inflammatory mediators such as inducible nitric oxide synthase (NOS), cyclooxygenase-2, interleukin-1 beta, and tumor necrosis factor alpha, and increases excitotoxic as well as ischemic neuronal death in vitro. Dexamethasone reduces HMGB1 dependent immune glia activation, having no effect on the protein's neurotoxic effects. HMGB1 is expressed in the nucleus of neurons and astrocytes of the mouse brain, and promptly (1 h) translocates into the cytoplasm of neurons within the ischemic brain. Brain microinjection of HMGB1 increases the transcript levels of proinflammatory mediators and sensitizes the tissue to the ischemic injury. Together, data underscore the neuropathological role of nuclear HMGB1, and point to the protein as a mediator of post-ischemic brain damage.