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Central role for endothelial human deneddylase-1/SENP8 in fine-tuning the vascular inflammatory response

Ehrentraut, SF;Kominsky, DJ;Glover, LE;Campbell, EL;Kelly, CJ;Bowers, BE;Bayless, AJ;Colgan, SP;

A deeper understanding of the mechanisms that control responses to inflammation is critical to the development of effective therapies. We sought to define the most proximal regulators of the Cullin (Cul)-RING ligases, which play a central role in the stabilization of NF-B and hypoxia-inducible factor (HIF). In these studies, we identify the human deneddylase-1 (SENP8) as a key regulator of Cul neddylation response in vitro and in vivo. Using human microvascular endothelial cells (HMECs), we examined inflammatory responses to LPS or TNF- by assessing Cul neddylation status, NF-B and HIF-1 stabilization, and inflammatory cytokine secretion. HMECs with an intact neddylation pathway showed a time-dependent induction of Cul-1 neddylation, nuclear translocation of NF-B, stabilization of HIF-1, and increased NF-B/HIF- promoter activity in response to LPS. HMECs lacking SENP8 were unable to neddylate Cul-1 and subsequently were unable to activate NF-B or HIF-1. Pharmacological targeting of neddylation (MLN4924) significantly abrogated NF-B responses, induced HIF-1 promoter activity, and reduced secretion of TNF--elicited proinflammatory cytokines. MLN4924 stabilized HIF and abrogated proinflammatory responses while maintaining anti-inflammatory IL-10 responses in vivo following LPS administration. These studies identify SENP8 as a proximal regulator of Cul neddylation and provide an important role for SENP8 in fine-tuning the inflammatory response. Moreover, our findings provide feasibility for therapeutic targeting of the Culs during inflammation.