Kawasaki disease: ubiquitin-specific protease 5 promotes endothelial inflammation via TNFα-mediated signaling

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 TNFα or KD sera. The inflammatory cytokine expression level and nuclear factor κB (NF-κB) 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 TNFα stimulation in HCAECs. Moreover, USP5 sustains proinflammatory cytokine production and NF-κB signaling activation, whereas USP5 knockdown causes the proinflammatory cytokine levels to decrease and suppress NF-κB signaling activation. Notably, the USP5 inhibitor vialinin A can suppress the expression of inflammatory genes induced by TNFα and IL-1β in HCAECs.

Conclusions: Our study identified USP5 as a positive regulator of TNFα 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 TNFα in vitro. USP5 promotes proinflammatory cytokine expression by sustaining NF-κB 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.