Laminar flow inhibits TNF-induced ASK1 activation by preventing dissociation of ASK1 from its inhibitor 14-3-3
Laminar flow inhibits TNF-induced ASK1 activation by preventing dissociation of ASK1 from its inhibitor 14-3-3
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DOI：
10.1172/jci11947
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发表时间：
2001-04-01
影响因子：
15.9
通讯作者：
Min, W
中科院分区：
文献类型：
--
作者：
Liu, YM;Yin, GY;Min, W
炎性细胞因子TNF-a刺激内皮细胞(ECs)中几个可能的促动脉粥样硬化信号事件，包括激活c-jun氨基末端激酶(JNK)和诱导E-选择素。在这里，黑麦表明，凋亡信号调节激酶1(ASK1)是一种MAP激酶，是肿瘤坏死因子介导的JNK激活所必需的。肿瘤坏死因子通过将ASK1从其抑制剂14-3-3中解离出来而激活ASK1。因为在稳定的层流区域动脉粥样硬化的风险降低，我们假设层流抑制促炎细胞因子介导的JNK的激活。稳定的层流可抑制ASK1和JNK的肿瘤坏死因子活性。FLOW对ASK1的抑制与ASK1与14-3-3的结合增加相关。缺乏14-3-3结合位点的ASK1的活性形式(ASK1-Delta NS367A)没有被Flow抑制。这些数据确立了ASK1作为Flow介导的细胞因子信号抑制的靶点，并表明14-3-3在ECs中作为抗炎介质的新作用。
The inflammatory cytokine TNF-a stimulates several presumed pro-atherogenic signaling events in endothelial cells (ECs), including activation of c-Jun NH2-terminal kinase (JNK) and induction of E-selectin. Here, rye show that apoptosis signal-regulating kinase 1 (ASK1), a MAP kinase kinase kinase, is required for TNF-mediated JNK activation. TNF activates ASK1 in part by dissociating ASK1 from its inhibitor 14-3-3. Because the risk of atherosclerosis is decreased in regions of steady laminar flow, we hypothesized that laminar flow inhibits proinflammatory cytokine-mediated activation of JNK. Steady laminar flow inhibited both TNF activation of ASK1 and JNK. Inhibition of ASK1 by flow correlated with increased association of ASK1 with 14-3-3. A constitutively active form of ASK1 lacking the 14-3-3-binding site (ASK1-Delta NS367A) was not inhibited by flow These data establish ASK1 as a target for flow-mediated inhibition of cytokine signaling and indicate a novel role for 14-3-3 as an anti-inflammatory mediator in ECs.