c-Jun N-terminal kinase attenuates TNFα signaling by reducing Nox1-dependent endosomal ROS production in vascular smooth muscle cells
c-Jun N-terminal kinase attenuates TNFα signaling by reducing Nox1-dependent endosomal ROS production in vascular smooth muscle cells
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DOI：
10.1016/j.freeradbiomed.2015.05.015
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发表时间：
2015-09-01
影响因子：
7.4
通讯作者：
Lamb, Fred S.
中科院分区：
文献类型：
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作者：
Choi, Hyehun;Dikaloya, Anna;Lamb, Fred S.
肿瘤坏死因子-α（INF α）是一种促炎细胞因子，可引起血管平滑肌细胞（VSMC）增殖和迁移，并促进炎性血管病变。TNF α激活核因子-κ B（NF-κ B）需要Nox 1产生内体超氧化物。在内皮细胞中，TNF α刺激c-Jun N-末端激酶（INK），其抑制NF-κ B信号传导。JNK负性调节TNF α诱导的NF-κ B活化的机制尚未明确。我们假设JNK通过Nox 1依赖性机制调节VSMC中NF-κ B的活化。TNF α诱导的NF-κ B活化是TNFR 1和内吞依赖性的。用显性负性发动蛋白（DynK 44 A）抑制内吞作用可增强TNF α诱导的JNK活化，但降低ERK活化，而p38激酶磷酸化没有改变。DynK 44 A减弱野生型（WT）VSMC细胞内、核内体超氧化物的产生，但在NADPH氧化酶1（Nox 1）敲除（KO）细胞中无此作用。靶向JNK 1或JNK 2的siRNA增强了WT细胞中TNF α诱导的NF-κ B激活，而JNK激活剂（茴香霉素）抑制了WT细胞中TNF α诱导的NF-κ B激活，但在Nox 1 KO细胞中无此作用。在WT中，JNK 1抑制增强了TNF α刺激的超氧化物生成，但在Nox 1 KO VSMC中则没有。这些数据表明JNK通过减少Nox 1依赖性内体ROS的产生来抑制对TNF α的炎症反应。JNK和内体超氧化物可能代表TNF α信号传导和血管炎症的药理学调节的新靶点。(C)2015 Elsevier Inc. All rights reserved.
Tumor necrosis factor-alpha (INF alpha), a proinflammatory cytokine, causes vascular smooth muscle cell (VSMC) proliferation and migration and promotes inflammatory vascular lesions. Nuclear factor-kappa B (NF-kappa B) activation by TNF alpha requires endosomal superoxide production by Nox1. In endothelial cells, TNFa stimulates c-Jun N-terminal kinase (INK), which inhibits NF-kappa B signaling. The mechanism by which JNK negatively regulates TNF alpha-induced NF-kappa B activation has not been defined. We hypothesized that JNK modulates NF-kappa B activation in VSMC, and does so via a Nox1-dependent mechanism. TNF alpha-induced NF-kappa B activation was TNFR1- and endocytosis-dependent. Inhibition of endocytosis with dominant-negative dynamin (DynK44A) potentiated TNF alpha-induced JNK activation, but decreased ERK activation, while p38 kinase phosphorylation was not altered. DynK44A attenuated intracellular, endosomal superoxide production in wild-type (WT) VSMC, but not in NADPH oxidase 1 (Nox1) knockout (KO) cells siRNA targeting JNK1 or JNK2 potentiated, while a JNK activator (anisomycin) inhibited, TNF alpha-induced NF-kappa B activation in WT, but not in Nox1 KO cells. TNF alpha-stimulated superoxide generation was enhanced by JNK1 inhibition in WT, but not in Nox1 KO VSMC. These data suggest that JNK suppresses the inflammatory response to TNF alpha by reducing Nox1-dependent endosomal ROS production. JNK and endosomal superoxide may represent novel targets for pharmacologic modulation of TNF alpha signaling and vascular inflammation. (C) 2015 Elsevier Inc. All rights reserved.