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首页> 外文期刊>American Journal of Physiology >Modulation of bone marrow-derived neutrophil signaling by H2O2: disparate effects on kinases, NF-kappaB, and cytokine expression.
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Modulation of bone marrow-derived neutrophil signaling by H2O2: disparate effects on kinases, NF-kappaB, and cytokine expression.

机译：H2O2对骨髓中性粒细胞信号的调节：对激酶，NF-κB和细胞因子表达的不同影响。

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摘要

Reactive oxygen species (ROS), including hydrogen peroxide (H2O2), are generated in increased amounts in pathological, biological processes and can play a role in signal transduction. Neutrophils often accumulate in acute inflammatory reactions, at sites where elevated concentrations of ROS are present. ROS have been demonstrated to participate in the activation of intracellular signaling pathways, including those involved in modulating nuclear accumulation and transcriptional activity of NF-kappaB. However, the role of ROS in affecting such events in neutrophils has not been examined. Using exposure of murine bone marrow neutrophils to H2O2 as a model of oxidative stress, we found both strong and persistent activation of ERK1/2, p38, JNK, and PKB, but not the p21-activated kinase. Stimulating the bone marrow-derived neutrophils with H2O2 did not affect nuclear translocation of NF-kappaB. However, production and secretion of the proinflammatory cytokine TNF-alpha in LPS-stimulated neutrophils were inhibited by H2O2. Exposure of LPS- or TNF-alpha-stimulated neutrophils to H2O2 decreased nuclear translocation of NF-kappaB. LPS-induced activation of the transcriptional factor AP-1 was also inhibited by H2O2. This inhibition of nuclear accumulation of NF-kappaB by H2O2 was not caused by an impaired capacity of LPS to stimulate the IKK pathway or to direct oxidative effects on NF-kappaB but rather reflected diminished degradation of IkappaB-alpha. These results indicate that oxidative stress, despite being able to selectively activate intracellular kinases in bone marrow-derived neutrophils, also inhibits NF-kappaB activation and associated TNF-alpha expression. Such inhibitory effects on neutrophil activation may limit tissue damage produced by oxidative stress.
机译：包括过氧化氢（H2O2）在内的活性氧（ROS）在病理，生物过程中的生成量增加，并且可以在信号转导中发挥作用。中性粒细胞经常在急性炎症反应中聚集在ROS浓度升高的部位。已经证明ROS参与细胞内信号传导途径的激活，包括那些参与调节NF-κB的核积累和转录活性的途径。然而，尚未研究ROS在中性粒细胞中影响此类事件的作用。使用鼠骨髓中性粒细胞暴露于H2O2作为氧化应激的模型，我们发现ERK1 / 2，p38，JNK和PKB均具有强而持久的激活，而p21激活的激酶则没有。用H2O2刺激源自骨髓的中性粒细胞不会影响NF-κB的核转运。然而，H2O2抑制LPS刺激的中性粒细胞中促炎性细胞因子TNF-α的产生和分泌。 LPS或TNF-α刺激的嗜中性粒细胞暴露于H2O2会降低NF-κB的核易位。 LPS诱导的转录因子AP-1的激活也被H2O2抑制。 H2O2对NF-kappaB核积累的抑制作用不是由LPS刺激IKK途径或指导对NF-kappaB的氧化作用的能力受损引起的，而是反映了IkappaB-alpha降解的减少。这些结果表明，氧化应激尽管能够选择性激活骨髓中性粒细胞中的细胞内激酶，但也能抑制NF-κB的激活和相关的TNF-α的表达。这种对嗜中性粒细胞活化的抑制作用可以限制由氧化应激产生的组织损伤。

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