DPP-4 exacerbates LPS-induced endothelial cells inflammation via integrin-51/FAK/AKT signaling

Endothelial dysfunction plays a pivotal role in the pathogenesis of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Dipeptidyl peptidase IV (DPP-4), a cell surface glycoprotein, has been implicated in endothelial inflammation and barrier dysfunction. In this study, the role of DPP-4 on lipopolysaccharide (LPS)induced pulmonary microvascular endothelial cells (HPMECs) dysfunction and the underlying mechanism were investigated by siRNA-mediated knockdown of DPP-4. Our results indicated that LPS (1 mu g/ml) challenge resulted in either the production and releasing of DPP-4, as well as the secretion of IL-6 and IL-8 in HPMECs. DPP-4 knockdown inhibited chemokine releasing and monolayer hyper-permeability in LPS challenged HPMECs. When cocultured with human polymorphonuclear neutrophils (PMNs), DPP4 knockdown suppressed LPSinduced neutrophil-endothelial adhesion, PMN chemotaxis and trans-endothelial migration. Western blotting showed that DPP-4 knockdown attenuated LPS-induced activation of TLR4/NF-kappa B pathway. Immunoprecipitation and liquid chromatography-tandem mass spectrometry revealed that DPP-4 mediated LPS-induced endothelial inflammation by interacting with integrin-alpha 5 beta 1. Moreover, exogenous soluble DPP-4 treatment sufficiently activated integrin-alpha 5 beta 1 downstream FAK/AKT/NF-kappa B signaling, thereafter inducing ICAM-1 upregulation in HPMECs. Collectively, our results suggest that endothelia synthesis and release DPP-4 under the stress of endotoxin, which interact with integrin-alpha 5 beta 1 complex in an autocrine or paracrine manner to exacerbate endothelial inflammation and enhance endothelial cell permeability. Therefore, blocking DDP-4 could be a potential therapeutic strategy to prevent endothelial dysfunction in ALI/ARDS.