Abrogation of NF-κB signaling in human neutrophils induces neutrophil survival through sustained p38-MAPK activation
Abrogation of NF-κB signaling in human neutrophils induces neutrophil survival through sustained p38-MAPK activation
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DOI：
10.1189/jlb.0809544
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发表时间：
2010-10-01
影响因子：
5.5
通讯作者：
Koenderman, Leo
中科院分区：
文献类型：
--
作者：
Langereis, Jeroen D.;Raaijmakers, Hanneke A. J. A.;Koenderman, Leo
nf - κ B是调控细胞炎症的重要转录因子，是新型抗炎疗法的主要靶点之一。如今，抗炎治疗主要依赖于类固醇，其作用之一是抑制nf - κ B活性。然而，类固醇在治疗中性粒细胞驱动的疾病（如COPD）方面的疗效有限。人类中性粒细胞在COPD的发病机制中发挥重要作用，通过细胞凋亡清除这些细胞是解决炎症的有效途径。在这项研究中，我们验证了人类中性粒细胞NF-kappa B通路的调节影响生存的假设。重要的是，药理NF-kappa B抑制剂Bay 11-7082如预期的那样抑制了人类中性粒细胞中的NF-kappa B信号传导。然而，我们发现10 μ M Bay 11-7082完全抑制NF-kappa B活性可显著延长中性粒细胞的存活时间，而其他信号通路的抑制剂没有观察到这一点。Bay 11-7082诱导的中性粒细胞存活依赖于p38- mapk激酶活性，因为p38激酶活性抑制剂SB203580完全消除了这种反应。Bay 11-7082诱导快速和持续的p38激活，与抑制NF-kappa B信号传导和延长中性粒细胞存活相关。NF-kappa B在调节p38-MAPK活化中的确切作用仍有待确定。在这些生存条件下，Bcl-xL的稳定性得到增强，而Mcl-1的稳定性没有增强。尽管抑制NF-kappa B会导致许多细胞类型中炎症基因的下调，但我们的研究结果表明，作为药物靶点，对中性粒细胞中基础NF-kappa B信号的干扰应谨慎使用。j . Leukoc。生物学报。88:655-664；2010.
NF-kappa B, an important transcription factor in the regulation of cellular inflammation, is one of the prime targets for novel anti-inflammatory therapeutics. Nowadays, anti-inflammatory therapies rely mostly on steroids, which among other effects, inhibit NF-kappa B activity. However, steroids have only limited efficacy in the treatment on neutrophil-driven diseases, such as COPD. Human neutrophils play an important role in the pathogenesis of COPD, and clearance of these cells by apoptosis is an effective pathway for resolution of inflammation. In this study, we tested the hypothesis that modulation of the NF-kappa B pathway in human neutrophils affects survival. Importantly, the pharmacological NF-kappa B inhibitor Bay 11-7082 inhibited NF-kappa B signaling in human neutrophils as expected. However, we found that complete inhibition of NF-kappa B activity with 10 mu M Bay 11-7082 prolonged neutrophil survival significantly, which was not observed with inhibitors for other signaling pathways. Bay 11-7082-induced neutrophil survival was dependent on p38-MAPK kinase activity, as the p38 kinase activity inhibitor SB203580 abrogated this response completely. Bay 11-7082 induced rapid and sustained p38 activation that correlated with inhibited NF-kappa B signaling and prolonged neutrophil survival. The precise role of NF-kappa B in regulation of p38-MAPK activation remains to be established. Under these conditions of survival, the stability of Bcl-xL but not Mcl-1 was enhanced. Although inhibition of NF-kappa B leads to down-regulation of inflammatory genes in many cell types, our results illustrate that interference with basal NF-kappa B signaling in neutrophils as a drug target should be used with caution. J. Leukoc. Biol. 88: 655-664; 2010.