Involvement of reactive oxygen species in cyclic stretch-induced NF-κB activation in human fibroblast cells
Involvement of reactive oxygen species in cyclic stretch-induced NF-κB activation in human fibroblast cells
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DOI：
10.1038/sj.bjp.0706182
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发表时间：
2005-06-01
影响因子：
7.3
通讯作者：
Sokabe, M
中科院分区：
文献类型：
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作者：
Amma, H;Naruse, K;Sokabe, M
1单轴周期性牵张通过牵张激活（SA）通道增加细胞内Ca 2+浓度和随后的人成纤维细胞核因子κ B（NF-κ B）激活导致环氧合酶（考克斯）-2上调。然而，关于升高的Ca 2+如何激活NF-κ B的信号传导机制尚不清楚。在这项研究中，我们检测了活性氧（ROS）作为中间信号的参与，它将升高的Ca 2+与NF-κ B激活联系起来。2 4-羟基-2-壬烯醛（HNE）的产生和修饰I κ B在2 min达到峰值。I κ B的磷酸化在8 min达到峰值。HNE修饰和I κ B磷酸化，NF-κ B易位到细胞核，以及随后的考克斯-2产生被细胞外Ca 2+去除或Gd 3+应用以及抗氧化剂抑制。3 I kappa B激酶（IKK）活性在牵张后4 min达到峰值，而牵张后4 min，3 I kappa B激酶（IKK）活性在牵张后4 min达到峰值，牵张后4 min，3 I kappa B激酶活性在牵张后4 min达到峰值，牵张后4 min，3 I kappa B激酶活性在牵张后4 min达到峰值，而牵张后4 min，3 I kappa B激酶活性在牵张后4 min达到峰值，牵张后4 min，3 I kappa B激酶活性在牵张后4 min达到峰值。IKK也是HNE修饰的，与I κ B相似，在2分钟时达到峰值。静态条件下的IKK被外源性应用的HNE以相对低的剂量（1 μ M）激活，而在较高浓度时被抑制，提示HNE可能是牵张诱导的NF-κ B B激活的候选信号之一。4本研究提示NF-κ B可能是牵张诱导的NF-κ B激活的候选信号之一。循环牵张引起的κ B活化由以下信号级联介导：SA通道活化->细胞内Ca 2+增加-> ROS产生-> IKK活化-> I κ B磷酸化-> NF-κ B转运至细胞核。
1 Uniaxial cyclic stretch leads to an upregulation of cyclooxygenase (COX)-2 through increases in the intracellular Ca2+ concentration via the stretch-activated (SA) channel and following nuclear factor kappa B (NF-kappa B)activation in human fibroblasts. However, the signaling mechanism as to how the elevated Ca2+ activates NF-kappa B is unknown. In this study, weexamined the involvement of reactive oxygen species (ROS) as an intermediate signal, which links the elevated Ca2+ with NF-kappa B activation.2 4-Hydroxy-2-nonenal (HNE) was produced and modified I kappa B peaking at 2 min. The phosphorylation of I kappa B peaked at 8min. HNE modification and I kappa B phosphorylation, NF-kappa B translocation to the nucleus, and following COX-2 production were inhibited by extracellular Ca2+ removal or Gd3+ application, as well as by the antioxidants. The stretch-inducedCa(2+) increase was inhibited by extracellular Ca2+ removal, or Gd3+ application.3 I kappa B kinase (IKK) activity peaked at 4 min, which was inhibited by extracellular Ca2+ removal, Gd3+ or the antioxidants. IKK was also HNE-modified and, similarly to I kappa B, peaked at 2 min. IKK under static conditions was activated by exogenously applied HNE at a relatively low dose (1 mu M), while it was inhibited at higher concentrations, suggesting thatHNE could be one of the candidate signals in the stretch-induced NF-kappa B activation.4 The present study suggests that the NF-kappa B activation by cyclic stretch is mediated by the following signal cascade: SA channel activation -> intracellular Ca2+ increase -> production of ROS -> activation of IKK -> phosphorylation of I kappa B -> NF-kappa B translocation to the nucleus.