Manganese modulates pro-inflammatory gene expression in activated glia
Manganese modulates pro-inflammatory gene expression in activated glia
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DOI：
10.1016/j.neuint.2005.12.020
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发表时间：
2006-07-01
影响因子：
4.2
通讯作者：
Chen, JH
中科院分区：
文献类型：
--
作者：
Chen, CJ;Ou, YC;Chen, JH
氧化还原活性金属对生物功能至关重要。它们的影响和细胞活动参与中枢神经系统（CNS）的生理和病理生理过程，包括炎症反应。锰是一种必需的微量元素，它是正常的生物活性和普遍存在的酶反应所必需的。然而，过量长期暴露于锰导致神经行为缺陷。最近的证据表明，锰的神经毒性涉及小胶质细胞或星形胶质细胞，代表性的中枢神经系统免疫细胞的激活。在这项研究中，我们评估了锰对原代大鼠皮质神经胶质细胞中促炎细胞因子和一氧化氮（NO）产生的调节作用的分子基础。培养的胶质细胞由85%的星形胶质细胞和15%的小胶质细胞组成。在测定的浓度范围内，锰不能诱导肿瘤坏死因子α（TNF-α）和诱导型一氧化氮合酶（iNOS）的表达，而它通过脂多糖γ-糖/干扰素γ-激活的神经胶质细胞增强iNOS和TNF-α基因的表达。这种增强伴随着游离锰的升高、氧化应激的产生、促分裂原活化蛋白激酶的活化以及NF-κ B和AP-1结合活性的增加。抑制性分子IKB-α的降解增强是锰增加NF-κ B活化的潜在机制之一。然而，锰降低iNOS酶活性可能是通过消耗辅因子，因为外源性四氢生物蝶呤逆转锰的作用。这些数据表明，锰可以通过不同的策略调节神经胶质炎症。(c)2006爱思唯尔有限公司保留所有权利。
Redox-active metals are of paramount importance for biological functions. Their impact and cellular activities participate in the physiological and pathophysiological processes of the central nervous system (CNS), including inflammatory responses. Manganese is an essential trace element and it is required for normal biological activities and ubiquitous enzymatic reactions. However, excessive chronic exposure to manganese results in neurobehavioral deficits. Recent evidence suggests that manganese neurotoxicity involves activation of microglia or astrocytes, representative CNS immune cells. In this study, we assessed the molecular basis of the effects of manganese on the modulation of pro-inflammatory cytokines and nitric oxide (NO) production in primary rat cortical glial cells. Cultured glial cells consisted of 85% of astrocytes and 15% of microglia. Within the assayed concentrations, manganese was unable to induce tumor necrosis factor alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS) expression, whereas it potentiated iNOS and TNF-alpha gene expression by lipopol gamma-saccharide/interferon-gamma-activated glial cells. The enhancement was accompanied by elevation of free manganese, generation of oxidative stress, activation of mitogen-activated protein kinases, and increased NF-KB and AP-1 binding activities. The potentiated degradation of inhibitory molecule IKB-alpha was one of underlying mechanisms for the increased activation of NF-KB by manganese. However, manganese decreased iNOS enzymatic activity possibly through the depletion of cofactor since exogenous tetrahydrobiopterin reversed manganese's action. These data indicate that manganese could modulate glial inflammation through variable strategies. (c) 2006 Elsevier Ltd. All rights reserved.