Inducible nitric oxide synthase expression is inhibited by myeloperoxidase
Inducible nitric oxide synthase expression is inhibited by myeloperoxidase
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DOI：
10.1016/j.niox.2005.04.002
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发表时间：
2005-08-01
影响因子：
3.9
通讯作者：
Reynolds, WF
中科院分区：
文献类型：
--
作者：
Kumar, AP;Ryan, C;Reynolds, WF
一氧化氮（NO）在血管舒张和宿主防御中起关键作用，但诱导型一氧化氮合酶（iNOS）在炎症部位过量产生NO也可能是致病的。在此，我们研究了MPO在IFN γ/LPS诱导的iNOS中的调节作用。在单核-巨噬细胞（M phi）与IL，MPO基因表达下调，iNOS被上调。在MPO敲除（KO）小鼠的M phi中，IL诱导的iNOS比MPO阳性细胞更早且更高，表明NIPO是抑制性的。与该解释一致，向培养的巨噬细胞中加入纯化的MPO酶抑制IL诱导的iNOS。此外，MPO酶的抑制剂4-氨基苯甲酰肼增强MPO阳性细胞中的iNOS诱导，但在MPO KO细胞中不增强。类似地，牛磺酸，NIPO产生的HOCl的清除剂，在MPO阳性细胞中增强iNOS诱导，但在MPO-KO细胞中不增强。MPO会影响早期事件，在IL后2小时内添加时会抑制iNOS的诱导，但在IL后几小时添加时则不会。NO供体硝普钠可减轻MPO的抑制作用，提示MPO的抑制作用是通过清除NO而实现的。这种解释与早期报道一致，即MPO消耗NO，并且低水平的NO供体增加IFN γ/LPS诱导的iNOS。这些发现的含义是，MPO作为看门人，抑制有害的诱导iNOS在炎症部位的非法信号。IFNy/LPS的联合信号传导通过抑制MPO基因表达来推翻守门人功能。(c)2005年爱思唯尔公司All rights reserved.
Nitric oxide (NO) plays key roles in vasodilation and host defense, yet the overproduction of NO by inducible nitric oxide synthase (iNOS) at inflammatory sites can also be pathogenic. Here, we investigate the role of MPO in modulating the induction of iNOS by IFN gamma/LPS IL). In monocyte-macrophages (M phi) treated with IL, MPO gene expression was found to be downregulated as iNOS was upregulated. In M phi from MPO-knockout (KO) mice, the induction of iNOS by IL was earlier and higher than in MPO-positive cells, suggesting NIPO is inhibitory. Consistent with that interpretation, the addition of purified MPO enzyme to cultured macrophages inhibited iNOS induction by IL. In addition, an inhibitor of MPO enzyme, 4-aminobenzohydrazide, enhanced iNOS induction in MPO-positive cells, but not in MPO-KO cells. Similarly, taurine, a scavenger of NIPO-generated HOCl, enhanced iNOS induction in MPO-positive cells, but not in MPO-KO cells. MPO affects an early event, suppressing iNOS induction when added within 2 h of IL, but not when added several hours after IL. The suppression by MPO was alleviated by NO donor, sodium nitroprusside, suggesting the suppression results from scavenging of NO by MPO. This interpretation is consistent with earlier reports that MPO consumes NO, and that low levels of NO donor augment induction of iNOS by IFN gamma/LPS. The implication of these findings is that MPO acts as gatekeeper, suppressing the deleterious induction of iNOS at inflammatory sites by illegitimate signals. The combined signaling of IFNy/LPS overrides the gatekeeper function by suppressing MPO gene expression. (c) 2005 Elsevier Inc. All rights reserved.