IPLA2B REGULATES VIRUS-INDUCED INDUCIBLE NO SYNTHASE EXPRESSION BY MACROPHAGES
IPLA2B 调节病毒诱导的巨噬细胞诱导型 NO 合酶表达
基本信息
- 批准号:7355239
- 负责人:
- 金额:$ 0.59万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-02-01 至 2007-01-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Recent evidence supports a regulatory role for the calcium-independent phospholipase A2 (iPLA2) in the antiviral response of inducible nitric-oxide synthase (iNOS) expression by macrophages. Because two mammalian isoforms of iPLA2 (iPLA2B and iPLA2?) have been cloned and characterized, the aim of this study was to identify the specific isoform(s) in macrophages that regulates the expression of iNOS in response to virus infection. Bromoenol lactone (BEL), a suicide substrate inhibitor of iPLA2, inhibits the activity of both isoforms at low micromolar concentrations. However, the R- and S-enantiomers of BEL display ~10-fold greater potency for inhibition of the enzymatic activity of iPLA2? and iPLA2B, respectively. In this study, we show that the iPLA2B-selective (S)-BEL inhibits encephalomyocarditis virus (EMCV)-induced iNOS expression, nitric oxide production, and iPLA2 enzymatic activity in macrophages in a concentration-related manner that closely resembles the inhibitory properties of racemic BEL. cAMP response element-binding protein (CREB) is one downstream target of iPLA2 that is required for the transcriptional activation of iNOS in response to virus infection, and consistent with the effects of BEL enantiomers on iNOS expression, (S)-BEL more effectively inhibits EMCV-induced CREB phosphorylation than (R)-BEL in macrophages. Using macrophages isolated from iPLA2B-null mice, virus infection fails to stimulate iNOS mRNA accumulation and protein expression, thus providing genetic evidence that iPLA2B is required for EMCV-induced iNOS expression. These findings provide evidence for a signaling role for iPLA2B in virus-induced iNOS expression by macrophages.
该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者(PI)可能从另一个NIH来源获得主要资金,因此可以在其他CRISP条目中表示。所列机构为中心,不一定是研究者所在机构。最近的证据支持钙非依赖性磷脂酶A2(iPLA 2)在巨噬细胞诱导型一氧化氮合酶(iNOS)表达的抗病毒反应中的调节作用。因为两种哺乳动物同种型的iPLA 2(iPLA 2B和iPLA 2?)已被克隆和表征,本研究的目的是鉴定巨噬细胞中响应病毒感染而调节iNOS表达的特异性同种型。溴烯醇内酯(BEL)是iPLA 2的自杀底物抑制剂,在低微摩尔浓度下抑制两种亚型的活性。然而,BEL的R-和S-对映体显示约10倍的抑制iPLA 2的酶活性的效力?ipla 2b分别。在这项研究中,我们表明,iPLA 2B选择性(S)-BEL抑制脑心肌炎病毒(EMCV)诱导的iNOS表达,一氧化氮的产生,和iPLA 2酶活性在巨噬细胞中的浓度相关的方式,非常类似于外消旋BEL的抑制特性。cAMP反应元件结合蛋白(CREB)是iPLA 2的下游靶点之一,其是响应病毒感染而转录激活iNOS所需的,并且与BEL对映体对iNOS表达的作用一致,在巨噬细胞中,(S)-BEL比(R)-BEL更有效地抑制EMCV诱导的CREB磷酸化。使用从iPLA 2B缺失小鼠分离的巨噬细胞,病毒感染不能刺激iNOS mRNA积累和蛋白表达,从而提供了iPLA 2B是EMCV诱导的iNOS表达所需的遗传证据。这些发现为iPLA 2B在病毒诱导的巨噬细胞iNOS表达中的信号传导作用提供了证据。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JASON M MORAN其他文献
JASON M MORAN的其他文献
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{{ truncateString('JASON M MORAN', 18)}}的其他基金
Regulation of molecular chaperones by a human virus
人类病毒对分子伴侣的调节
- 批准号:
7157239 - 财政年份:2006
- 资助金额:
$ 0.59万 - 项目类别:
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