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首页> 外文期刊>Infection and immunity >Induction of Inducible Nitric Oxide Synthase-NO·?by Lipoarabinomannan ofMycobacterium tuberculosis Is Mediated by MEK1-ERK, MKK7-JNK, and NF-κB Signaling Pathways
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Induction of Inducible Nitric Oxide Synthase-NO·?by Lipoarabinomannan ofMycobacterium tuberculosis Is Mediated by MEK1-ERK, MKK7-JNK, and NF-κB Signaling Pathways

机译：MEK1-ERK，MKK7-JNK和NF-κB信号通路介导结核分枝杆菌脂寡糖甘露聚糖诱导的一氧化氮合酶-NO·α的诱导

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Nitric oxide (NO·?) expression by inducible nitric oxide synthase (iNOS) is an important host defense mechanism againstMycobacterium tuberculosis in mononuclear phagocytes. The objective of this investigation was to examine the role of mitogen-activated protein (MAP) kinase (MAPK) and nuclear factor κB (NF-κB) signaling pathways in the regulation of iNOS and NO·?by a mycobacterial cell wall lipoglycan known as mannose-capped lipoarabinomannan (ManLAM). Specific pharmacologic inhibition of the extracellular-signal-regulated kinase (ERK) or NF-κB pathway revealed that both these signaling cascades were required in gamma interferon (IFN-γ)-ManLAM-induced iNOS protein and NO2 ? expression in mouse macrophages. Transient cotransfection of dominant-negative protein mutants of the c-Jun NH2-terminal kinase (JNK) pathway revealed that the MAP kinase kinase 7 (MKK7)-JNK cascade also mediated IFN-γ–ManLAM induction of iNOS promoter activity whereas MKK4 did not. Overexpression of null mutant IκBα, a potent inhibitor of NF-κB activation, confirmed that the IκBα kinase (IKK)–NF-κB signaling pathway enhanced IFN-γ–ManLAM-induced iNOS promoter activity. By contrast, activated p38mapk inhibited iNOS induction. These results indicate that combined IFN-γ and ManLAM stimulation induced iNOS and NO·?expression and that MEK1-ERK, MKK7-JNK, IKK–NF-κB, and p38mapksignaling pathways play important regulatory roles.
机译：诱导型一氧化氮合酶（iNOS）表达一氧化氮（NO·α）是单核吞噬细胞中针对结核分枝杆菌的重要宿主防御机制。这项研究的目的是检查有丝分裂原活化蛋白（MAP）激酶（MAPK）和核因子κB（NF-κB）信号通路在分枝杆菌细胞壁脂多糖iNOS和NO·α调控中的作用。甘露糖封端的脂质阿拉伯甘露聚糖（ManLAM）。细胞外信号调节激酶（ERK）或NF-κB途径的特异性药理抑制作用表明，这两种信号级联都是γ干扰素（IFN-γ）-ManLAM诱导的iNOS蛋白和NO 2 ？在小鼠巨噬细胞中的表达。 c-Jun NH 2 -末端激酶（JNK）途径的显性负性蛋白突变体的瞬时共转染显示，MAP激酶激酶7（MKK7）-JNK级联也介导了IFN-γ–ManLAM的诱导iNOS启动子活性的变化，而MKK4没有。无效突变体IκBα的过表达（一种有效的NF-κB激活抑制剂）证实了IκBα激酶（IKK）–NF-κB信号通路增强了IFN-γ–ManLAM诱导的iNOS启动子活性。相比之下，激活的p38 mapk 抑制了iNOS的诱导。这些结果表明，IFN-γ和ManLAM联合刺激可诱导iNOS和NO·α的表达，MEK1-ERK，MKK7-JNK，IKK-NF-κB和p38 mapk 信号通路起着重要的调节作用。

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