Distinct signaling pathways for induction of type IINOS by IFN-γ and LPS in BV-2 microglial cells
Distinct signaling pathways for induction of type IINOS by IFN-γ and LPS in BV-2 microglial cells
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DOI：
10.1016/j.neuint.2005.03.007
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发表时间：
2005-09-01
影响因子：
4.2
通讯作者：
Sun, GY
中科院分区：
文献类型：
--
作者：
Shen, SM;Yu, S;Sun, GY
小胶质细胞激活时释放的一氧化氮(NO)参与了许多神经退行性疾病的组织损伤和细胞死亡。最近的研究表明，干扰素-γ(IFN-γ)和脂多糖(LPS)能够独立地诱导BV-2小胶质细胞11型一氧化氮合酶(INOS)的表达和NO的产生。然而，这两种药物激活iNOS的信号通路之间的详细比较还没有完成。对PKC亚型的分析表明，BV-2细胞中主要存在PKC Delta、L和X。虽然干扰素-γ和脂多糖均能特异性地增强PKC-Delta的酪氨酸磷酸化水平，但干扰素-γ可诱导磷酸化的PKC-Delta在1h内稳定升高，而内毒素处理只能短暂地提高磷酸化-PKC-Delta的水平，峰值出现在5min。PKC Delta的特异性抑制剂Rottlerin可剂量依赖性地抑制干扰素-γ和脂多糖诱导的NO生成。尽管有PKC Delta的共同参与，但干扰素-γ而不是内毒素诱导的NO产生涉及细胞外信号调节蛋白1/2(ERK1/2)级联反应，而干扰素-γ诱导的ERK1/2的磷酸化是通过PKC介导的。另一方面，内毒素而不是干扰素通过刺激核转录因子-kappaB的活化和核移位与DNA相互作用而诱导NO的产生。这些结果揭示了干扰素-γ和脂多糖诱导BV-2小胶质细胞诱导型一氧化氮合酶的不同信号通路。(C)2005爱思唯尔有限公司。保留所有权利。
Nitric oxide,(NO) release upon microglial cell activation has been implicated in the tissue injury and cell death in many neurodegenerative diseases Recent studies have indicated the ability of interferon-gamma (IFN gamma) and lipopolysaccharides (LPS) to independently induce type 11 nitric oxide synthase (iNOS) expression and NO production in BV-2 microglial cells. However, a detailed comparison between the signaling pathways activating iNOS by these two agents has not been accomplished. Analysis of PKC isoforms revealed mainly the presence of PKC delta, L and X in BV-2 cells. Although both IFN gamma and LPS could specifically enhance the tyrosine phosphorylation of PKC delta, treatment with IFN gamma induced a steady increase of phospho-PKC delta for up to 1 h, whereas treatment with LPS elevated phospho-PKC delta levels only transiently, with peak activity at 5 min. Rottlerin, a specific inhibitor for PKC delta, dose-dependently inhibited IFN gamma- and LPS-induced NO production. Despite the common involvement of PKC delta, IFN gamma- but not LPS-induced NO production involved extracellular signal-regulated kinases (ERK1/2) cascade and IFN gamma-induced phosphorylation of ERK1/2 was mediated through PKC. On the other hand, LPS- but not IFN gamma-induced NO production was through stimulation of NF-kappa B activation and nuclear translocation to interact with DNA. These results demonstrated distinct signaling pathways for induction of iNOS by IFN gamma and LPS in BV-2 microglial cells. (c) 2005 Elsevier Ltd. All rights reserved.