Kawasaki disease: ubiquitin-specific protease 5 promotes endothelial inflammation via TNFα-mediated signaling
Kawasaki disease: ubiquitin-specific protease 5 promotes endothelial inflammation via TNFα-mediated signaling
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川崎病：泛素特异性蛋白酶 5 通过 TNFα 介导的信号传导促进内皮炎症
DOI：
10.1038/s41390-022-02341-z
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发表时间：
2022-11-03
影响因子：
3.6
通讯作者：
Lv, Haitao
中科院分区：
文献类型：
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作者：
Huang, Chengcheng;Wang, Wang;Lv, Haitao
本研究旨在探讨泛素特异性蛋白酶5（ubiquitin-specific protease 5，USP 5）在川崎（Kawasaki disease，KD）血管内皮炎症中的作用。方法检测TNF α或KD血清刺激后HCAEC中USP 5的表达水平。采用USP 5过表达/敲低慢病毒及其小分子抑制剂vialinin A，检测HCAECs中炎性细胞因子表达水平和核因子-κ B（NF-κ B）信号转导激活蛋白的表达。结果KD血清刺激HCAECs后，USP 5表达上调。类似地，在HCAEC中，在TNF α刺激后，USP 5表达水平也以时间和剂量依赖性方式增加。此外，USP 5维持促炎细胞因子产生和NF-κ B信号传导激活，而USP 5敲低导致促炎细胞因子水平降低并抑制NF-κ B信号传导激活。值得注意的是，USP 5抑制剂vialinin A可以抑制HCAEC中TNF α和IL-1 β诱导的炎症基因的表达。结论我们的研究确定USP 5是HCAEC炎症反应期间TNF α产生及其下游信号激活的正调节因子，并证明其抑制剂小瓶宁A可能作为KD治疗的候选药物，以防止促炎细胞因子的过度产生。Impact USP 5在体外与急性KD血清或TNF α孵育的人冠状动脉内皮细胞（HCAEC）中上调。USP 5通过维持HCAEC中NF-κ B信号传导激活来促进促炎细胞因子表达。USP 5抑制剂vialinin A可抑制HCAEC中促炎细胞因子的表达水平，从而为KD治疗提供了新的机制和干预策略。
Background This study aimed to explore the functions of ubiquitin-specific protease 5 (USP5) in the endothelial inflammation of Kawasaki disease (KD). Methods USP5 expression levels in HCAECs were examined after stimulation with TNF alpha or KD sera. The inflammatory cytokine expression level and nuclear factor kappa B (NF-kappa B) signaling activation proteins were also investigated in HCAECs by using USP5 overexpression/knockdown lentivirus as well as its small molecule inhibitor vialinin A. Results USP5 expression level is upregulated in HCAECs after stimulation with KD sera. Similarly, the USP5 expression level is also increased in a time- and dose-dependent manner upon TNF alpha stimulation in HCAECs. Moreover, USP5 sustains proinflammatory cytokine production and NF-kappa B signaling activation, whereas USP5 knockdown causes the proinflammatory cytokine levels to decrease and suppress NF-kappa B signaling activation. Notably, the USP5 inhibitor vialinin A can suppress the expression of inflammatory genes induced by TNF alpha and IL-1 beta in HCAECs. Conclusions Our study identified USP5 as a positive regulator of TNF alpha production and its downstream signaling activation during the inflammatory responses in HCAECs, and demonstrated that its inhibitor vialinin A might serve as a candidate drug for KD therapy to prevent the excessive production of proinflammatory cytokines. Impact USP5 is upregulated in human coronary artery endothelial cells (HCAECs) whether incubated with acute KD sera or TNF alpha in vitro. USP5 promotes proinflammatory cytokine expression by sustaining NF-kappa B signaling activation in HCAECs. The USP5 inhibitor vialinin A can suppress the expression levels of proinflammatory cytokines in HCAEC, thus providing a novel mechanism and intervention strategy in KD therapy.